Substituted oxazolidinones and their use in the field of blood coagulation

ABSTRACT

The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) 
                         
processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.

This application is a 371 of PCT/EP00/12492 filed 11 Dec. 2000.

The present invention relates to the field of blood coagulation. Inparticular, the present invention relates to novel oxazolidinonederivatives, to processes for their preparation and to their use asactive compounds in medicaments.

Blood coagulation is a protective mechanism of the organism which helpsto “seal” defects in the wall of the blood vessels quickly and reliably.Thus, loss of blood can be avoided or kept to a minimum. Haemostasisafter injury of the blood vessels is effected mainly by the coagulationsystem in which an enzymatic cascade of complex reactions of plasmaproteins is triggered. Numerous blood coagulation factors are involvedin this process, each of which factors converts, on activation, therespectively next inactive precursor into its active form. At the end ofthe cascade comes the conversion of soluble fibrinogen into insolublefibrin, resulting in the formation of a blood clot. In bloodcoagulation, traditionally the intrinsic find the extrinsic system,which end in a joint reaction path, are distinguished. Here factor Xa,which is formed from the proenzyme factor X, plays a key role, since itconnects the two coagulation paths. The activated serine protease Xacleaves prothrombin to thrombin. The resulting thrombin, in turn,cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. Inaddition, thrombin is a potent effector of platelet aggregation whichlikewise contributes significantly to haemostasis.

Maintenance of normal haemostasis—between bleeding and thrombosis—issubject to a complex regulatory mechanism. Uncontrolled activation ofthe coagulant system or defective inhibition of the activation processesmay cause formation of local thrombi or embolisms in vessels (arteries,veins, lymph vessels) or in heart cavities. This may lead to seriousdisorders, such as myocardial infarct, angina pectoris (includingunstable angina), reocclusions and restenoses after angioplasty oraortocoronary bypass, stroke, transitory ischaemic attacks, peripheralarterial occlusive disorders, pulmonary embolisms or deep venousthromboses; hereinbelow, these disorders are collectively also referredto as thromboembolic disorders. In addition, in the case of consumptioncoagulopathy, hypercoagulability may—systemically—result in disseminatedintravascular coagulation.

These thromboembolic disorders are the most frequent cause of morbidityand mortality in most industrialized countries (Pschyrembel, KlinischesWörterbuch [clinical dictionary], 257^(th) edition, 1994, Walter deGruyter Verlag, page 199 ff., entry “Blutgerinnung” [blood coagulation];Römpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart,entry “Blutgerinnung”; Lubert Stryer, Biochemie [biochemistry], Spektrumder Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259ff.).

The anticoagulants, i.e. substances for inhibiting or preventing bloodcoagulation, which are known from the prior art have various, oftengrave disadvantages. Accordingly, in practice, an efficient treatmentmethod or prophylaxis of thromboembolic disorders is very difficult andunsatisfactory.

In the therapy and prophylaxis of thromboembolic disorders, use isfirstly made of heparin, which is administered parenterally orsubcutaneously. Owing to more favourable pharmacokinetic properties,preference is nowadays more and more given to low-molecular-weightheparin; however, even with low-molecular-weight heparin, it is notpossible to avoid the known disadvantages described below, which areinvolved in heparin therapy. Thus, heparin is ineffective whenadministered orally and has a relatively short half-life. Since heparininhibits a plurality of factors of the blood coagulation cascade at thesame time, the action is nonselective. Moreover, there is a high risk ofbleeding; in particular, brain haemorrhages and gastrointestinalbleeding may occur, which may result in thrombopenia, drug-inducedalopecia or osteoporosis (Pschyrembel, Klinisches Wörterbuch, 257^(th)edition, 1994, Walter de Gruyter Verlag, page 610, entry “Heparin”;Römpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart,entry “Heparin”).

A second class of anticoagulants are the vitamin K antagonists. Theseinclude, for example, 1,3-indanediones, and especially compounds such aswarfarin, phenprocoumon, dicumarol and other coumarin derivatives whichinhibit the synthesis of various products of certain vitamin K-dependentcoagulation factors in the liver in a non-selective manner. Owing to themechanism of action, however, the onset of the action is very slow(latency to the onset of action 36 to 48 hours). It is possible toadminister the compounds orally; however, owing to the high risk ofbleeding and the narrow therapeutic index, a time-consuming individualadjustment and monitoring of the patient are required. Moreover, otheradverse effects, such as gastrointestinal disturbances, hair loss andskin necroses, have been described (Pschyrembel, Klinisches Wörterbuch,257^(th) edition, 1994, Walter de Gruyter Verlag, page 292 ff., entry“coumarin derivatives”; Ullmann's Encyclopedia of Industrial Chemistry,5^(th) edition, VCH Verlagsgesellschaft, Weinheim, 1985–1996, entry“vitamin K”).

Recently, a novel therapeutic approach for the treatment and prophylaxisof thromboembolic disorders has been described. This novel therapeuticapproach aims to inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J.Hauptmann, J. Stürzebecher, Thrombosis Research 1999, 93, 203; F.Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by classical andcombinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, J. A. Ostrem,Factor Xa inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser,Thrombin and factor Xa inhibitors, Drugs of the Future 1998, 23, 423; A.Uzan, Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R.M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1 (1),63). It has been shown that, in animal models, various both peptidic andnonpeptidic compounds are effective as factor Xa inhibitors.

Accordingly, it is an object of the present invention to provide novelsubstances for controlling disorders, which substances have a widetherapeutic spectrum.

In particular, they should be suitable for a more efficient prophylaxisand/or treatment of thromboembolic disorders, avoiding—at least to someextent—the disadvantages of the prior art described above, where theterm “thromboembolic disorders” in the context of the present inventionis to be understood as meaning, in particular, serious disorders, suchas myocardial infarct, angina pectoris (including unstable angina),reocclusions and restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischaemic attacks, peripheral arterial occlusivedisorders, pulmonary embolisms or deep venous thromboses.

It is another object of the present invention to provide novelanticoagulants which inhibit the blood coagulation factor Xa withincreased selectivity, avoiding—at least to some extent—the problems ofthe therapeutic methods for thromboembolic disorders known from theprior art.

Accordingly, the present invention provides substituted oxazolidinonesof the general formula (I)

in which:

-   R¹ represents optionally benzo-fused thiophene (thienyl) which may    optionally be mono- or polysubstituted;-   R² represents any organic radical;-   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each    represents hydrogen or represents (C₁–C₆)-alkyl    and their pharmaceutically acceptable salts, hydrates and prodrugs,    except for compounds of the general formula (I) in which the radical    R¹ is an unsubstituted 2-thiophene radical and the radical R² is    simultaneously a mono- or polysubstituted phenyl radical and the    radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

Preference is given here to compounds of the general formula (I),

in which

-   R¹ represents optionally benzo-fused thiophene (thienyl) which may    optionally be mono- or polysubstituted by a radical from the group    consisting of halogen; cyano; nitro; amino; aminomethyl;    (C₁–C₈)-alkyl which for its part may optionally be mono- or    polysubstituted by halogen; (C₃–C₇)-cycloalkyl; (C₁–C₈)-alkoxy;    imidazolinyl; —C(═NH)NH₂; carbamoyl; and mono- and    di-(C₁–C₄)-alkyl-aminocarbonyl,-   R² represents one of the groups below:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents (C₆–C₁₄)-aryl, preferably        (C₆–C₁₀)-aryl, in particular phenyl or naphthyl, very        particularly preferably phenyl;    -    the radical “B” represents a 5- or 6-membered aromatic        heterocycle which contains up to 3 heteroatoms and/or hetero        chain members, in particular up to 2 heteroatoms and/or hetero        chain members, from the group consisting of S, N, NO (N-oxide)        and O;    -    the radical “D” represents a saturated or partially        unsaturated, mono- or bicyclic, optionally benzo-fused 4- to        9-membered heterocycle which contains up to three heteroatoms        and/or hetero chain members from the group consisting of S, SO,        SO₂, N, NO (N-oxide) and O;    -    the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—,        —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—,        —OOC—, —S—, —SO₂— or represents a covalent bond;    -    where    -    the groups “A”, “B” and “D” defined above may each optionally        be mono- or polysubstituted by a radical from the group        consisting of halogen; trifluoromethyl; oxo; cyano; nitro;        carbamoyl; pyridyl; (C₁–C₆)-alkanoyl; (C₃–C₇)-cycloalkanoyl;        (C₆–C₁₄)-arylcarbonyl; (C₅–C₁₀)-heteroarylcarbonyl;        (C₁–C₆)-alkanoyloxymethyloxy; (C₁–C₄)-hydroxy-alkylcarbonyl;        —COOR²⁷; —SO₂R²⁷; C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹;        —OR³⁰; —NR³⁰OR³¹, (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl,        -   where (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl for their part            may optionally be substituted by a radical from the group            consisting of cyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸)            and —C(NR²⁷R²⁸)═NR²⁹,    -    where:        -   v is either 0 or 1 and        -   R²⁷, R²⁸ and R²⁹ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl, (C₃–C₇)-cycloalkyl, (C₁–C₄)-alkanoyl,            carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or        -   R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom            to which they are attached form a saturated or partially            unsaturated 5- to 7-membered heterocycle having up to three,            preferably up to two, identical or different heteroatoms            from the group consisting of N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            (C₃–C₇)-cycloalkyl, (C₁–C₄)-alkylsulphonyl,            (C₁–C₄)-hydroxyalkyl, (C₁–C₄)-aminoalkyl,            di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl, —CH₂C(NR²⁷R²⁸)═NR²⁹ or            —COR³³,        -    where            -   R³³ represents (C₁–C₆)-alkoxy,                (C₁–C₄)-alkoxy-(C₁–C₄)-alkyl,                (C₁–C₄)-alkoxycarbonyl-(C₁–C₄)-alkyl,                (C₁–C₄)-aminoalkyl, (C₁–C₄)-alkoxycarbonyl,                (C₁–C₄)-alkanoyl-(C₁–C₄)-alkyl, (C₃–C₇)-cycloalkyl,                (C₁–C₆)-alkenyl, (C₁–C₈)-alkyl, which may optionally be                substituted by phenyl or acetyl, (C₆–C₁₄)-aryl,                (C₅–C₁₀)-heteroaryl, trifluoromethyl, tetrahydrofuranyl                or butyrolactone,    -   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each        represents hydrogen or represents (C₁–C₆)-alkyl        and their pharmaceutically acceptable salts, hydrates and        prodrugs,        except for compounds of the general formula (I) in which the        radical R¹ is an unsubstituted 2-thiophene radical and the        radical R² is simultaneously a mono- or polysubstituted phenyl        radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each        simultaneously hydrogen.

Preference is also given here to compounds of the general formula (I),

in which

-   R¹ represents thiophene (thienyl), in particular 2-thiophene, which    may optionally be mono- or polysubstituted by halogen, preferably    chlorine or bromine, by amino, aminomethyl or (C₁–C₈)-alkyl,    preferably methyl, where the (C₁–C₈)-alkyl radical for its part may    optionally be mono- or polysubstituted by halogen, preferably    fluorine,-   R² represents one of the groups below:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents (C₆–C₁₄)-aryl, preferably        (C₆–C₁₀)-aryl, in particular phenyl or naphthyl, very        particularly preferably phenyl;        -   -   -   the radical “B” represents a 5- or 6-membered                    aromatic heterocycle which contains up to 3                    heteroatoms and/or hetero chain members, in                    particular up to 2 heteroatoms and/or hetero chain                    members, from the group consisting of S, N, NO                    (N-oxide) and O;    -    the radical “D” represents a saturated or partially unsaturated        4 to 7-membered heterocycle which contains up to three        heteroatoms and/or hetero chain members from the group        consisting of S, SO, SO₂, N, NO (N-oxide) and O;    -    the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—,        —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—,        —OOC—, —S— or represents a covalent bond;    -    where    -    the groups “A”, “B” and “D” defined above may in each case        optionally be mono- or polysubstituted by a radical from the        group consisting of halogen; trifluoromethyl; oxo; cyano; nitro;        carbamoyl; pyridyl; (C₁–C₆)-alkanoyl; (C₃–C₇)-cycloalkanoyl;        (C₆–C₁₄)-arylcarbonyl; (C₅–C₁₀)-heteroarylcarbonyl;        (C₁–C₆)-alkanoyloxymethyloxy; —COOR²⁷; —SO₂R²⁷;        —C(NR²⁷R²⁸)═NR²⁹; —CONR R²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹,        (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl,        -   where (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl for their part            may optionally be substituted by a radical from the group            consisting of cyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸)            and —C(NR²⁷R²⁸)═NR²⁹,    -    where:        -   v is either 0 or 1 and        -   R²⁷, R²⁸ and R²⁹ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl or (C₃–C₇)-cycloalkyl, and/or        -   R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom            to which they are attached form a saturated or partially            unsaturated 5- to 7-membered heterocycle having up to three,            preferably up to two, identical or different heteroatoms            from the group consisting of N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            (C₃–C₇)-cycloalkyl, (C₁–C₄)-alkylsulphonyl,            (C₁–C₄)-hydroxyalkyl, (C₁–C₄)-aminoalkyl,            di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl, (C₁–C₄)-alkanoyl,            (C₆–C₁₄)-arylcarbonyl, (C₅–C₁₀)-heteroarylcarbonyl,            (C₁–C₄)-alkylaminocarbonyl or —CH₂C(NR²⁷R²⁸)═NR²⁹,    -   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each        represents hydrogen or represents (C₁–C₆)-alkyl        and their pharmaceutically acceptable salts, hydrates and        prodrugs,        except for compounds of the general formula (I) in which the        radical R¹ is an unsubstituted 2-thiophene radical and the        radical R² is simultaneously a mono- or polysubstituted phenyl        radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each        simultaneously hydrogen.

Particular preference is given here to compounds of the general formula(I),

in which

-   R¹ represents thiophene (thienyl), in particular 2-thiophene, which    may optionally be mono- or polysubstituted by halogen, preferably    chlorine or bromine, or by (C₁–C₈)-alkyl, preferably methyl, where    the (C₁–C₈)-alkyl radical for its part may optionally be mono- or    polysubstituted by halogen, preferably fluorine,-   R² represents one of the groups below:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents phenyl or naphthyl, in particular        phenyl; the radical “B” represents a 5- or 6-membered aromatic        heterocycle which contains up to 2 heteroatoms from the group        consisting of S, N, NO (N-oxide) and O;    -    the radical “D” represents a saturated or partially unsaturated        5- or 6-membered heterocycle which contains up to two        heteroatoms and/or hetero chain members from the group        consisting of S, SO, SO₂, N, NO (N-oxide) and O;    -    the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—,        —OCH₂—, —CH₂O—, —CONH—, —NHCO— or represents a covalent bond;    -    where    -    the groups “A”, “B” and “D” defined above may in each case        optionally be mono- or polysubstituted by a radical from the        group consisting of halogen; trifluoromethyl; oxo; cyano;        pyridyl; (C₁–C₃)-alkanoyl; (C₆–C₁₀)-arylcarbonyl;        (C₅–C₆)-heteroarylcarbonyl; (C₁–C₃)-alkanoyloxymethyloxy;        —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹;        (C₁–C₄)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,        -   where (C₁–C₄)-alkyl and cyclopropyl, cyclopentyl or            cyclohexyl for their part may optionally be substituted by a            radical from the group consisting of cyano; —OH; —OCH₃;            —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹,    -    where:        -   v is either 0 or 1, preferably 0, and            -   R²⁷, R²⁸ and R²⁹ are identical or different and                independently of one another each represents hydrogen,                (C₁–C₄)-alkyl or else cyclopropyl, cyclopentyl or                cyclohexyl    -    and/or    -    R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to        which they are attached may form a saturated or partially        unsaturated 5- to 7-membered heterocycle having up to two        identical or different heteroatoms from the group consisting of        N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            cyclopropyl, cyclopentyl, cyclohexyl,            (C₁–C₄)-alkylsulphonyl, (C₁–C₄)-hydroxyalkyl,            (C₁–C₄)-aminoalkyl, di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl,            (C₁–C₃)-alkanoyl or phenylcarbonyl,-   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each    represents hydrogen or represents (C₁–C₆)-alkyl    and their pharmaceutically acceptable salts, hydrates and prodrugs,    except for compounds of the general formula (I) in which the radical    R¹ is an unsubstituted 2-thiophene radical and the radical R² is    simultaneously a mono- or polysubstituted phenyl radical and the    radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

Particular preference is given here to compounds of the general formula(I),

in which

-   R¹ represents 2-thiophene which may optionally be substituted in the    5-position by a radical from the group consisting of chlorine,    bromine, methyl or trifluoromethyl,-   R² represents one of the groups below:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents phenyl or naphthyl, in particular        phenyl;    -    the radical “B” represents a 5- or 6-membered aromatic        heterocycle which contains up to 2 heteroatoms from the group        consisting of S, N, NO (N-oxide) and O;    -    the radical “D” represents a saturated or partially unsaturated        5- or 6-membered heterocycle which contains a nitrogen atom and        optionally a further heteroatom and/or hetero chain member from        the group consisting of S, SO, SO₂ and O; or contains up to two        heteroatoms and/or hetero chain members from the group        consisting of S, SO, SO₂ and O;    -    the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—,        —OCH₂—, —CH₂O—, —CONH—, —NHCO— or represents a covalent bond;    -    where    -    the groups “A”, “B” and “D” defined above may in each case        optionally be mono- or polysubstituted by a radical from the        group consisting of halogen; trifluoromethyl; oxo; cyano;        pyridyl; (C₁–C₃)-alkanoyl; (C₆–C₁₀)-arylcarbonyl;        (C₅–C₆)-heteroarylcarbonyl; (C₁–C₃)-alkanoyloxymethyloxy;        —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹; (C₁–C₄)-alkyl; and        cyclopropyl, cyclopentyl or cyclohexyl,        -   where (C₁–C₄)-alkyl and cyclopropyl, cyclopentyl or            cyclohexyl for their part may optionally be substituted by a            radical from the group consisting of cyano; —OH; —OCH₃;            —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹,    -    where:        -   v is either 0 or 1, preferably 0, and        -   R²⁷, R²⁸ and R²⁹ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl    -    and/or        -   R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom            to which they are attached may form a saturated or partially            unsaturated 5- to 7-membered heterocycle having up to two            identical or different heteroatoms from the group consisting            of N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            cyclopropyl, cyclopentyl, cyclohexyl,            (C₁–C₄)-alkylsulphonyl, (C₁–C₄)-hydroxyalkyl,            (C₁–C₄)-aminoalkyl, di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl,            (C₁–C₃)-alkanoyl or phenylcarbonyl,    -   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each        represents hydrogen or represents (C₁–C₄)-alkyl        and their pharmaceutically acceptable salts, hydrates and        prodrugs,        except for compounds of the general formula (I) in which the        radical R¹ is an unsubstituted 2-thiophene radical and the        radical R² is simultaneously a mono- or polysubstituted phenyl        radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each        simultaneously hydrogen.

Very particular preference is given here to compounds of the generalformula (I),

in which

-   R¹ represents 2-thiophene which is substituted in the 5-position by    a radical from the group consisting of chlorine, bromine, methyl and    trifluoromethyl,-   R² represents D-A-:    -   where:    -   the radical “A” represents phenylene;    -   the radical “D” represents a saturated 5- or 6-membered        heterocycle,    -   which is attached to “A” via a nitrogen atom,    -   which has a carbonyl group directly adjacent to the linking        nitrogen atom and    -   in which one carbon ring member may be replaced by a heteroatom        from the group consisting of S, N and O;    -   where    -   the group “A” defined above may optionally be mono- or        disubstituted in the meta position with respect to the point of        attachment to the oxazolidinone, by a radical from the group        consisting of fluorine, chlorine, nitro, amino, trifluoromethyl,        methyl and cyano,-   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ each represent hydrogen    and their pharmaceutically acceptable salts, hydrates and prodrugs.

Very particular preference is also given here to the compound having thefollowing formula

and to its pharmaceutically acceptable salts, hydrates and prodrugs.

In the compounds of the general formula (I) above, the radical

-   R¹ may in particular represent optionally benzo-fused thiophene    (thienyl) which may optionally be mono- or polysubstituted by a    radical from the group consisting of halogen; cyano; nitro;    (C₁–C₈)-alkyl, which for its part may optionally be mono- or    polysubstituted by halogen; (C₃–C₇)-cycloalkyl; (C₁–C₈)-alkoxy;    imidazolinyl; —C(═NH)NH₂; carbamoyl; and mono- and    di-(C₁–C₄)-alkylaminocarbonyl.

In the compounds of the general formula (I), the radical

-   R¹ may preferably represent thiophene (thienyl), in particular    2-thiophene, which may optionally be mono- or polysubstituted by    halogen, preferably chlorine or bromine, or by (C₁–C₈)-alkyl,    preferably methyl, where the (C₁–C₈)-alkyl radical, preferably the    methyl radical, may for its part optionally be mono- or    polysubstituted by halogen, preferably fluorine.

In the compounds of the general formula (I), the radicals

-   R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be identical or different and may    represent, in particular, hydrogen or (C₁–C₆)-alkyl, preferably    hydrogen or (C₁–C₄)-alkyl, very particularly preferably hydrogen.

The radical R², i.e. the organic radical, can in particular be selectedfrom the substituent groups listed below:

In the compounds of the general formula (I), the radical

-   R² may, in particular, represent a group of the following formula:    Y—X′—(CH₂)_(p)—X—(CO)_(n)—(CH₂)_(o) ₁ —(CR⁹R¹⁰)_(m)—(CH₂)_(o) ₂ —-    where:    -   m is an integer from 0 to 6, preferably from 1 to 3,    -   n is either 0 or 1,    -   p is an integer from 0 to 3, preferably either 0 or 1,    -   o₁ is an integer 0 or 1,    -   o₂ is an integer 0 or 1,    -   R⁹ and R¹⁰ are identical or different and each represents        hydrogen; (C₁–C₄)-alkyl, preferably methyl; (C₁–C₄)-alkoxy,        preferably methoxy; (C₃–C₇)-cycloalkyl; hydroxyl or fluorine,    -   X and X′ are identical or different and each represents O; N—R¹¹        or a covalent bond,-    where R¹¹ represents H; (C₁–C₄)-alkyl, preferably methyl, or    (C₃–C₇)-cycloalkyl,    -   Y represents a 3- to 7-membered saturated or partially        unsaturated cyclic hydrocarbon radical which optionally contains        1 to 3 identical or different heteroatoms and/or hetero chain        members from the group consisting of N, O, S, SO and SO₂,    -    where:    -    this radical Y may optionally be substituted by a 5- or        6-membered aromatic or a 3- to 7-membered saturated or partially        unsaturated cyclic hydrocarbon radical which optionally contains        up to 3 identical or different heteroatoms from the group        consisting of N, O and S and    -    where this radical may for its part optionally be substituted        by a radical from the group consisting of cyano; hydroxyl;        halogen; (C₁–C₄)-alkyl; —C(═NR¹²)NR¹³R¹³; and —NR¹⁴R¹⁵,    -    where:        -   R¹² represents hydrogen, (C₁–C₄)-alkyl or            (C₃–C₇)-cycloalkyl;        -   R¹³ and R^(13′) are identical or different and independently            of one another each represents hydrogen, (C₁–C₄)-alkyl or            (C₃–C₇)-cycloalkyl        -    and/or        -   R¹³ and R^(13′) together with the N atom to which they are            attached form a 5- to 7-membered heterocycle which may            optionally contain up to 2 further heteroatoms from the            group consisting of N, O and S;        -   R¹⁴ and R¹⁵ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            (C₃–C₇)-cycloalkyl or (C₁–C₅)-alkanoyl;        -    and/or        -    this radical Y may furthermore optionally be substituted by            a radical from the group consisting of oxo; cyano; thiono;            halogen; —OR¹⁶; ═NR¹⁶; —NR¹⁶R¹⁷; —C(═NR¹⁸)NR¹⁹R^(19′) and            (C₁–C₄)-alkyl,        -    in which (C₁–C₄)-alkyl for its part may optionally be            substituted by a radical from the group consisting of            hydroxyl; cyano; —NR¹⁶R¹⁷ and —C(═NR¹⁸)NR¹⁹R^(19′),        -    where:            -   R¹⁶ and R¹⁷ are identical or different and independently                of one another each represents hydrogen, (C₁–C₄)-alkyl,                (C₃–C₇)-cycloalkyl or (C₁–C₃)-alkanoyl;            -   R¹⁸ represents hydrogen, (C₁–C₄)-alkyl or                (C₃–C₇)-cycloalkyl;            -   R¹⁹ and R^(19′) are identical or different and                independently of one another each represents hydrogen,                (C₁–C₄)-alkyl or (C₃–C₇)-cycloalkyl and/or            -   R¹⁹ and R^(19′) together with the N atom to which they                are attached form a 5- to 7-membered heterocycle which                may optionally contain up to 2 further heteroatoms from                the group consisting of N, O and S.

Particular preference is given to compounds of the general formula (I)in which the radical

-   R² represents a group of the following formula:    Y—X′—(CH₂)_(p)—X—(CO)_(n)—(CH₂)_(o) ₁ —(CR⁹R¹⁰)_(m)—(CH₂)_(o) ₂ —-    where    -   m is an integer from 0 to 3,    -   n is an integer 0 or 1,    -   p is an integer 0 or 1,    -   o₁ is an integer 0 or 1,    -   o₂ is an integer 0 or 1,    -   R⁹ and R¹⁰ are identical or different and each represents        hydrogen; methyl; methoxy; hydroxyl or fluorine,    -   X and X′ are identical or different and each represents O; N—R¹¹        or a covalent bond,    -    where R¹¹ represents H or methyl,    -   Y represents a 5- to 7-membered saturated cyclic hydrocarbon        radical which optionally contains 1 or 2 identical or different        heteroatoms and/or hetero chain members from the group        consisting of N, O, S, SO and SO₂, in particular cyclohexyl,        piperazinyl, morpholinyl, thiomorpholinyl, diazepinyl,        pyrrolidinyl and piperidinyl,    -    where:    -    this radical Y may optionally be substituted by a 5- or        6-membered aromatic or a 5- to 7-membered saturated or partially        unsaturated cyclic hydrocarbon radical which optionally contains        up to 2 identical or different heteroatoms from the group        consisting of N, O and S and    -    where this radical for its part may be substituted by a radical        from the group consisting of cyano; hydroxyl; fluorine;        chlorine; (C₁–C₄)-alkyl; —C(═NR¹²)NR¹³R^(13′); and —NR¹⁴R¹⁵,    -    where:        -   R¹² represents hydrogen, methyl, ethyl, cyclopropyl,            cyclopentyl or cyclohexyl;        -   R¹³ and R^(13′) are identical or different and independently            of one another each represents hydrogen, methyl, ethyl,            cyclopropyl, cyclopentyl or cyclohexyl and/or        -   R¹³ and R^(13′) together with the N atom to which they are            attached form a 5- to 7-membered heterocycle which may            optionally contain up to 2 further heteroatoms from the            group consisting of N, O and S, in particular piperidinyl,            piperazinyl, morpholinyl and thiomorpholinyl;        -   R¹⁴ and R¹⁵ are identical or different and independently of            one another each represents hydrogen, methyl, ethyl,            cyclopropyl, cyclopentyl or cyclohexyl or else acetyl;        -    and/or        -    this radical Y may furthermore optionally be substituted by            a radical from the group consisting of oxo; cyano; thiono;            fluorine; chlorine; —OH; —OCH₃; ═NR¹⁶; —NH₂; —N(CH₃)₂;            —C(═NR¹⁸)NR¹⁹R^(19′) and methyl,        -    in which methyl for its part may optionally be substituted            by a radical from the group consisting of hydroxyl; cyano;            —NR¹⁶R¹⁷ and —C(═NR¹⁸)NR¹⁹R^(19′),        -    where:            -   R¹⁶ and R¹⁷ are identical or different and independently                of one another each represents hydrogen, methyl,                (C₃–C₇)-cycloalkyl or acetyl;            -   R¹⁸ represents hydrogen, methyl or (C₃–C₇)-cycloalkyl;            -   R⁹ and R^(19′) are identical or different and                independently of one another each represents hydrogen,                methyl or (C₃–C₇)-cycloalkyl            -    and/or            -   R¹⁹ and R^(19′) together with the N atom to which they                are attached form a 5- to 7-membered heterocycle which                may optionally contain up to 2 further heteroatoms from                the group consisting of N, O and S, in particular                piperidinyl, piperazinyl, morpholinyl and                thio-morpholinyl.

Likewise, in the compounds of the general formula (I), the radical

-   R² may represent a group of the formula below:    Z—(CO)_(t)—(CR²⁰R²¹)_(s)—    -   where:    -   s is an integer from 1 to 6,    -   t is either 0 or 1,    -   R²⁰ and R²¹ are identical or different and each represents        hydrogen, (C₁–C₄)-alkyl, (C₁–C₄)-alkoxy, (C₃–C₇)-cycloalkyl,        hydroxyl or fluorine,    -   Z represents a radical which is selected from the group        consisting of cyano; —C(NR²²R²³)═NR²⁴; —CO(NH)_(u)NR²²R²³; and        —NR²⁵R²⁶,    -    where:        -   u is either 0 or 1, preferably 0, and        -   R²², R²³ and R²⁴ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl or (C₃–C₇)-cycloalkyl, preferably hydrogen or            methyl, and/or        -   R²² and R²³ together with the N atom to which they are            attached form a 5- to 7-membered heterocycle which may            optionally contain up to 2 further heteroatoms and/or hetero            chain members from the group consisting of N, O, S, SO and            SO₂;        -   R²⁵ and R²⁶ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl or            (C₃–C₇)-cycloalkyl, preferably hydrogen, methyl or ethyl,            where (C₁–C₄)-alkyl and (C₃–C₇)-cycloalkyl for their part            may optionally be substituted by hydroxyl or (C₁–C₆)-alkoxy.

Furthermore, in the compounds of the general formula (I), the radical

-   R² may represent one of the following groups:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents (C₆–CI₄)-aryl, preferably        (C₆–C₁₀)-aryl, in particular phenyl or naphthyl, very        particularly preferably phenyl;    -    the radical “B” represents a 5- or 6-membered aromatic        heterocycle which contains up to 3 heteroatoms and/or hetero        chain members, in particular up to 2 heteroatoms and/or hetero        chain members, from the group consisting of S, N, NO (N-oxide)        and O;    -    the radical “D” represents a saturated or partially unsaturated        4- to 7-membered heterocycle which contains up to three        heteroatoms and/or hetero chain members from the group        consisting of S, SO, SO₂, N, NO (N-oxide) and O;    -    the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—,        —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—,        —OOC—, —S— or represents a covalent bond;    -    where    -    the groups “A”, “B” and “D” defined above may in each case        optionally be mono- or polysubstituted by a radical from the        group consisting of halogen; trifluoromethyl; oxo; cyano; nitro;        carbamoyl; pyridyl; (C₁–C₆)-alkanoyl; (C₃–C₇)-Cycloalkanoyl;        (C₆–C₁₄)-arylcarbonyl; (C₅–C₁₀)-heteroarylcarbonyl;        (C₁–C₆)-alkanoyloxymethyloxy; —COOR²⁷; —SO₂R²⁷;        —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹,        (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl,    -    where (C₁–C₆)-alkyl and (C₃–C₇)-cycloalkyl for their part may        optionally be substituted by a radical from the group consisting        of cyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and        —C(NR²⁷R²⁸)═NR²⁹,    -    where:        -   v is either 0 or 1 and        -   R²⁷, R²⁸ and R²⁹ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl or (C₃–C₇)-cycloalkyl and/or        -   R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom            to which they are attached form a saturated or partially            unsaturated 5- to 7-membered heterocycle having up to three,            preferably up to two, identical or different heteroatoms            from the group consisting of N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            (C₃–C₇)-cycloalkyl, (C₁–C₄)-alkyl-sulphonyl,            (C₁–C₄)-hydroxyalkyl, (C₁–C₄)-aminoalkyl,            di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl, (C₁–C₄)-alkanoyl,            (C₆–C₁₄)-arylcarbonyl, (C₅–C₁₀)-heteroarylcarbonyl,            (C₁–C₄)-alkylaminocarbonyl or —CH₂C(NR²⁷R²⁸)═NR²⁹.

Preference is also given to compounds of the general formula (I) inwhich the radical

-   R² represents one of the groups below:    -   A-,    -   A-M-,    -   D-M-A-,    -   B-M-A-,    -   B-,    -   B-M-,    -   B-M-B-,    -   D-M-B-,    -    where:    -    the radical “A” represents phenyl or naphthyl, in particular        phenyl;    -    the radical “B” represents a 5- or 6-membered aromatic        heterocycle which contains up to 2 heteroatoms from the group        consisting of S, N, NO (N-oxide) and O;    -    the radical “D” represents a saturated or partially unsaturated        5- or 6-membered heterocycle which contains up to two        heteroatoms and/or hetero chain members from the group        consisting of S, SO, SO₂, N, NO (N-oxide) and O;    -    the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—,        —OCH₂—, —CH₂O—, —CONH—, —NHCO— or represents a covalent bond;    -    where    -   the groups “A”, “B” and “D” defined above may in each case        optionally be mono- or polysubstituted by a radical from the        group consisting of halogen; trifluoromethyl; oxo; cyano;        pyridyl; (C₁–C₃)-alkanoyl; (C₆–C₁₀)-arylcarbonyl;        (C₅–C₆)-heteroarylcarbonyl; (C₁–C₃)-alkanoyloxymethyloxy;        —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹;        (C₁–C₄)—, alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,    -    where (C₁–C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl        for their part may optionally be substituted by a radical from        the group consisting of cyano; —OH; —OCH₃; —NR²⁸R²⁹;        —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁹)═NR²⁹,    -    where:        -   v is either 0 or 1, preferably 0, and        -   R²⁷, R²⁸ and R²⁹ are identical or different and            independently of one another each represents hydrogen,            (C₁–C₄)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl            and/or        -   R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom            to which they are attached may form a saturated or partially            unsaturated 5- to 7-membered heterocycle having up to two            identical or different heteroatoms from the group consisting            of N, O and S, and        -   R³⁰ and R³¹ are identical or different and independently of            one another each represents hydrogen, (C₁–C₄)-alkyl,            cyclopropyl, cyclopentyl, cyclohexyl,            (C₁–C₄)-alkylsulphonyl, (C₁–C₄)-hydroxyalkyl,            (C₁–C₄)-aminoalkyl, di-(C₁–C₄)-alkylamino-(C₁–C₄)-alkyl,            (C₁–C₃)-alkanoyl or phenylcarbonyl.

Likewise, in the compounds of the general formula (I), the radical

-   R² may represent a group of the following formula:

-   -   R³² represents hydrogen or (C₁–C₄)-alkyl, preferably hydrogen or        methyl, and    -   W represents S, NH or O, preferably S.

Moreover, in the compounds of the general formula (I), the radical

-   R² may be a group of the formula below

Finally, in the compounds of the general formula (I), the radical

-   R² may be a group of the formula below

To date, oxazolidinones have essentially only been described asantibiotics, and in individual cases also as MAO inhibitors andfibrinogen antagonists (review: Riedl, B., Endermann, R., Exp. Opin.Ther. Patents 1999, 9 (5), 625), where a small 5-[acyl-aminomethyl]group (preferably 5-[acetylaminomethyl]) appears to be essential for theantibacterial activity.

Substituted aryl- and heteroarylphenyloxazolidinones in which a mono- orpolysubstituted phenyl radical may be attached to the N atom of theoxazolidinone ring and which may have an unsubstitutedN-methyl-2-thiophenecarboxamide radical in the 5-position of theoxazolidinone ring, and their use as antibacterial substances, are knownfrom U.S. Pat. Nos. 5,929,248, 5,801,246, 5,756,732, 5,654,435,5,654,428 and 5,565,571.

In addition, benzamidine-containing oxazolidinones are known assynthetic intermediates in the synthesis of factor Xa inhibitors and/orfibrinogen antagonists (WO-A-99/31092, EP-A-623615).

Depending on the substitution pattern, the compounds of the generalformula (I) according to the invention may exist in stereoisomeric formswhich are either like image and mirror image (enantiomers) or not likeimage and mirror image (diastereomers). The invention relates both tothe enantiomers or diastereomers and to their respective mixtures. Theracemic forms, like the diastereomers, can be separated in a knownmanner into the stereoisomerically uniform components.

Furthermore, certain compounds of the general formula (I) can be presentin tautomeric forms. This is known to the person skilled in the art, andsuch compounds are likewise within the scope of the invention.

Physiologically acceptable, i.e. pharmaceutically compatible, salts canbe salts of the compounds according to the invention with inorganic ororganic acids. Preference is given to salts with inorganic acids, suchas, for example, hydrochloric acid, hydrobromic acid, phosphoric acid orsulphuric acid, or to salts with organic carboxylic or sulphonic acids,such as, for example, acetic acid, trifluoroacetic acid, propionic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Other pharmaceutically compatible salts which may be mentioned are saltswith customary bases, such as, for example, alkali metal salts (forexample sodium or potassium salts), alkaline earth metal salts (forexample calcium or magnesium salts) or ammonium salts, derived fromammonia or organic amines, such as, for example, diethylamine,triethylamine, ethyldiisopropylamine, procaine, dibenzylamine,N-methylmorpholine, dihydroabietylamine or methylpiperidine.

According to the invention, “hydrates” are forms of the compounds of thegeneral formula (I) above which form a molecule compound (solvate) inthe solid or liquid state by hydration with water. In the hydrates, thewater molecules are attached through secondary valencies byintermolecular forces, in particular hydrogen bridges. Solid hydratescontain water as so-called crystal water in stoichiometric ratios, wherethe water molecules do not have to be equivalent with respect to theirbinding state. Examples of hydrates are sesquihydrates, monohydrates,dihydrates or trihydrates. Equally suitable are the hydrates of salts ofthe compounds according to the invention.

According to the invention, “prodrugs” are forms of the compounds of thegeneral formula (I) above which for their part can be biologicallyactive or inactive, but which can be converted into the correspondingbiologically active form (for example metabolically, solvolytically orin another way).

Halogen represents fluorine, chlorine, bromine and iodine. Preference isgiven to chlorine or fluorine.

(C₁–C₈)-Alkyl represents a straight-chain or branched alkyl radicalhaving 1 to 8 carbon atoms. Examples which may be mentioned are: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andn-hexyl. The corresponding alkyl groups with fewer carbon atoms, suchas, for example, (C₁–C₆)-alkyl and (C₁–C₄)-alkyl, are derivedanalogously from this definition. In general, preference is given to(C₁–C₄)-alkyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, alkylsulphonyl, hydroxyalkyl,hydroxyalkylcarbonyl, alkoxyalkyl, alkoxycarbonyl-alkyl, alkanoylalkyl,aminoalkyl or alkylaminoalkyl is likewise derived from this definition.

(C₃–C₇)-Cycloalkyl represents a cyclic alkyl radical having 3 to 7carbon atoms. Examples which may be mentioned are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The correspondingcycloalkyl groups having fewer carbon atoms, such as, for example,(C₃–C₅)-cycloalkyl, are derived analogously from this definition.Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, cycloalkanoyl, is likewise derivedfrom this definition.

In the context of the invention, (C₂–C₆)-alkenyl represents astraight-chain or branched alkenyl radical having 2 to 6 carbon atoms.Preference is given to a straight-chain or branched alkenyl radicalhaving 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl,allyl, isopropenyl and n-but-2-en-1-yl.

(C₁–C₈)-Alkoxy represents a straight-chain or branched alkoxy radicalhaving 1 to 8 carbon atoms. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. Thecorresponding alkoxy groups having fewer carbon atoms, such as, forexample, (C₁–C₆)-alkoxy and (C₁–C₄)-Alkoxy, are derived analogously fromthis definition. In general, preference is given to (C₁–C₄)-alkoxy.

The meaning of the corresponding component of other more complexsubstituents, such as, for example alkoxy-alkyl, alkoxycarbonyl-alkyland alkoxycarbonyl, is likewise derived from this definition.

Mono- or di-(C₁–C₄)-alkylaminocarbonyl represents an amino group whichis attached via a carbonyl group and which has a straight-chain orbranched or two identical or different straight-chain or branched alkylsubstitutents having in each case 1 to 4 carbon atoms. Examples whichmay be mentioned are: methylamino, ethylamino, n-propylamino,isopropylamino, t-butylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.

(C₁–C₆)-Alkanoyl represents a straight-chain or branched alkyl radicalhaving 1 to 6 carbon atoms which carries a doubly attached oxygen atomin the 1-position and is attached via the 1-position. Examples which maybe mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl,pivaloyl, n-hexanoyl. The corresponding alkanoyl groups with fewercarbon atoms, such as, for example, (C₁–C₅)-alkanoyl, (C₁–C₄)-alkanoyland (C₁–C₃)-alkanoyl, are derived analogously from this definition. Ingeneral, preference is given to (C₁–C₃)-alkanoyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, cycloalkanoyl and alkanoylalkyl, islikewise derived from this definition.

(C₃–C₇)-Cycloalkanoyl represents a cycloalkyl radical having 3 to 7carbon atoms as, defined above which is attached via a carbonyl group.

(C₁–C₆)-Alkanoyloxymethyloxy represents a straight-chain or branchedalkanoyloxymethyloxy radical having 1 to 6 carbon atoms. Examples whichmay be mentioned are: acetoxymethyloxy, propionoxymethyloxy,n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy,n-hexanoyloxymethyloxy. The corresponding alkanoyloxymethyloxy groupshaving fewer carbon atoms, such as, for example,(C₁–C₃)-alkanoyloxymethyloxy, are derived analogously from thisdefinition. In general, preference is given to(C₁–C₃)-alkanoyloxymethyloxy.

(C₆–C₁₄)-Aryl represents an aromatic radical having 6 to 14 carbonatoms. Examples which may be mentioned are: phenyl, naphthyl,phenanthrenyl and anthracenyl. The corresponding aryl groups with fewercarbon atoms, such as, for example, (C₆–C₁₀)-aryl are derivedanalogously from this definition. In general, preference is given to(C₆–C₁₀)-aryl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, arylcarbonyl, is likewise derivedfrom this definition.

(C₅–C₁₀)-Heteroaryl or a 5- to 10-membered aromatic heterocycle havingup to 3 heteroatoms and/or hetero chain members from the groupconsisting of S, O, N and NO (N-oxide) represents a mono- or bicyclicheteroaromatic which is attached via a carbon ring atom of theheteroaromatic or, if appropriate, via a nitrogen ring atom of theheteroaromatic. Examples which may be mentioned are: pyridyl, pyridylN-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl,indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl,isoquinolyl, naphthyridinyl, quinazolinyl. The correspondingheterocycles having a smaller ring size, such as, for example, 5- or6-membered aromatic heterocycles, are derived analogously from thisdefinition. In general, preference is given to 5- or 6-membered aromaticheterocycles, such as, for example, pyridyl, pyridyl N-oxide, pyrimidyl,pyridazinyl, furyl and thienyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, (C₅–C₁₀)-heteroarylcarbonyl, islikewise derived from this definition.

A 3- to 9-membered saturated or partially unsaturated, mono- orbicyclic, optionally benzo-fused heterocycle having up to 3 heteroatomsand/or hetero chain members from the group consisting of S, SO, SO₂, N,NO (N-oxide) and O represents a heterocycle which may contain one ormore double bonds, which may be mono- or bicyclic, to which a benzenering may be fused to two adjacent carbon ring atoms and which isattached via a carbon ring atom or a nitrogen ring atom. Examples whichmay be mentioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl,morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl, and1,4-diazepinyl. Preference is given to piperidinyl, morpholinyl andpyrrolidinyl.

The corresponding cycles having a smaller ring size, such as, forexample, 5- to 7-membered cycles, are derived analogously from thisdefinition.

The present invention also provides a process for preparing thecompounds of the general formula (I) according to the invention whereeither, according to one process alternative

-   [A] compounds of the general formula (II)

-    in which-    the radicals R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined    above,-    are reacted with carboxylic acids of the general formula (III)

-    in which    -   the radical R¹ is as defined above,    -   or else with the corresponding carbonyl halides, preferably        carbonyl chlorides, or else with the corresponding symmetric or        mixed carboxylic anhydrides of the carboxylic acids of the        general formula (III) defined above    -   in inert solvents, if appropriate in the presence of an        activating or coupling agent and/or a base, to give compounds of        the general formula (I)

-   -    in which        -   the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as            defined above,

-    or else according to a process alternative

-   [B] compounds of the general formula (IV)

-    in which-    the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined    above,    -   are converted, using a suitable selective oxidizing agent in an        inert solvent, into the corresponding epoxide of the general        formula (V)

-   -    in which        -   the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as            defined above,    -   and, by reaction in an inert solvent, if appropriate in the        presence of a catalyst, with an amine of the general formula        (VI)        R²—NH₂  (VI),    -    in which        -   the radical R² is as defined above,    -   the compounds of the general formula (VII)

-   -    in which        -   the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as            defined above,    -   are initially prepared and    -   subsequently, in an inert solvent in the presence of phosgene or        phosgene equivalents, such as, for example, carbonyldiimidazole        (CDI), cyclized to give the compounds of the general formula (I)

-   -    in which        -   the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as            defined above,    -   where—both for process alternative [A] and for process        alternative [B]—in the case where R² contains a 3- to 7-membered        saturated or partially unsaturated cyclic hydrocarbon radical        having one or more identical or different heteroatoms from the        group consisting of N and S, an oxidation with a selective        oxidizing agent to afford the corresponding sulphone, sulphoxide        or N-oxide may follow    -   and/or    -   where—both for process alternative [A] and for process        alternative [B]—in the case where the compound prepared in this        manner has a cyano group in the molecule, an amidination of this        cyano group by customary methods may follow    -   and/or    -   where—both for process alternative [A] and for process        alternative [B]—in the case where the compound prepared in this        manner has a BOC amino protective group in the molecule, removal        of this BOC amino protective group by customary methods may        follow    -   and/or    -   where—both for process alternative [A] and for process        alternative [B]—in the case where the compound prepared in this        manner has an aniline or benzylamine radical in the molecule, a        reaction of this amino group with various reagents such as        carboxylic acids, carboxylic anhydrides, carbonyl chlorides,        isocyanates, sulphonyl chlorides or alkyl halides to give the        corresponding derivatives may follow    -   and/or    -   where—both for process alternative [A] and for process        alternative [B]—in the case where the compound prepared in this        manner has a phenyl ring in the molecule, a reaction with        chlorosulphonic acid and subsequent reaction with amines to give        the corresponding sulphonamides may follow.

The processes according to the invention can be illustrated in anexemplary manner by the equations below:

The oxidation step described above, which is optional, can beillustrated in an exemplary manner by the equation below:

Suitable solvents for the processes described above are organic solventswhich are inert under the reaction conditions. These include halogenatedhydrocarbons, such as dichloromethane, trichloromethane, carbontetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane,1,2-dichloroethylene or trichloroethylene, ethers, such as diethylether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethyleneglycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene,xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethylsulphoxide, acetonitrile, pyridine, hexamethylphosphoric triamide orwater.

It is also possible to use solvent mixtures of the solvents mentionedabove.

Suitable activating or coupling agents for the processes described aboveare the reagents which are customarily used for this purpose, forexample N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide·HCl,N,N′-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole·H₂O and thelike.

Suitable bases are the customary inorganic or organic bases. Thesepreferably include alkali metal hydroxides, such as, for example, sodiumhydroxide or potassium hydroxide, or alkali metal carbonates, such assodium carbonate or potassium carbonate, or sodium methoxide orpotassium methoxide or sodium ethoxide or potassium ethoxide orpotassium-tert-butoxide, or amides, such as sodium amide, lithiumbis-(trimethylsilyl)amide or lithium diisopropylamide, or amines, suchas triethylamine, diisopropylethylamine, diisopropylamine,4-N,N-dimethylaminopyridine or pyridine.

The base can be employed here in an amount of from 1 to 5 mol,preferably from 1 to 2 mol, based on 1 mol of the compounds of thegeneral formula (II).

The reactions are generally carried out in a temperature range of from−78° C. to reflux temperature, preferably in the range from 0° C. toreflux temperature.

The reactions can be carried out at atmospheric, elevated or reducedpressure (for example in the range from 0.5 to 5 bar). In general, thereactions are carried out at atmospheric pressure.

Suitable selective oxidizing agents, both for the preparation of theepoxides and for the optional oxidation to give the sulphone, sulphoxideor N-oxide, are m-chloroperbenzoic acid (MCPBA), sodium metaperiodate,N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acid or osmiumtetroxide.

With respect to the preparation of the epoxides, the preparationconditions which are customary for this purpose are employed.

With respect to more detailed process conditions for the optionaloxidation to give the sulphone, sulphoxide or N-oxide, reference is madeto the following literature: M. R. Barbachyn et al., J. Med. Chem. 1996,39, 680 and WO-A-97/10223.

Furthermore, reference is made to Examples 14 to 16 given in theexperimental part.

The optional amidation is carried out under customary conditions. Formore details, reference is made to Examples 31 to 35 and 140 to 147.

The compounds of the general formulae (II), (III), (IV) and (VI) areknown per se to the person skilled in the art or can be prepared bycustomary methods. For oxazolidinones, in particular the5-(aminomethyl)-2-oxooxazolidines required, cf. WO-A-98/01446;WO-A-93/23384; WO-A-97/03072; J. A. Tucker et al., J. Med. Chem. 1998,41, 3727; S. J. Brickner et al., J. Med. Chem. 1996, 39, 673; W. A.Gregory et al., J. Med. Chem. 1989, 32, 1673.

The compounds of the general formula (a) according to the invention havean unforeseeable useful pharmacological activity spectrum and aretherefore particularly suitable for the prophylaxis and/or treatment ofdisorders.

The compounds of the general formula (I) according to theinvention—including the compounds which are excluded by disclaimer fromthe chemical product protection—act in particular as anticoagulants andcan therefore preferably be employed in medicaments for the prophylaxisand/or therapy of thromboembolic disorders. For the purpose of thepresent invention, “thromboembolic disorders” include, in particular,serious disorders such as myocardial infarct, angina pectoris (includingunstable angina), reocclusions and restenoses after angioplasty oraortocoronary bypass, stroke, transitory ischaemic attacks, peripheralarterial occlusion disorders, pulmonary embolisms or deep venousthromboses.

Furthermore, the compounds of the general formula (I) according to theinvention—including the compounds which are excluded by disclaimer fromthe, chemical product protection—are also suitable for treatingdisseminated intravascular coagulation (DIC).

Finally, the compounds of the general formula (I) according to theinvention—including the compounds which are excluded by disclaimer fromthe chemical product protection—are also suitable for the prophylaxisand/or treatment of atherosclerosis and arthritis, and additionally alsofor the prophylaxis and/or treatment of Alzheimer's disease and cancer.

The compounds of the general formula (I) according to theinvention—including the compounds excluded by disclaimer from thechemical product protection—act in particular as selective inhibitors ofthe blood coagulation factor Xa and do not inhibit, or only inhibit atconsiderably higher concentrations, other serine proteases as well, suchas thrombin, plasmin or trypsin.

In the context of the present invention, inhibitors of the bloodcoagulation factor Xa in which the IC₅₀ values for the factor Xainhibition are lower by a factor of 100, preferably by a factor of 500,in particular by a factor of 1000, than the IC₅₀ values for theinhibition of other serine proteases, in particular thrombin, plasminand trypsin, are referred to as being “selective”, where with a view tothe test methods for selectivity, reference is made to the test methodsof Examples A-1) a.1) and a.2) described below.

The compounds of the general formula (I) according to theinvention—including the compounds which are excluded by disclaimer fromthe chemical product protection—can furthermore be used for preventingcoagulation ex vivo, for example for banked blood or biological sampleswhich contain factor Xa.

The present invention thus provides oxazolidinones of the formula (I)effecting in particular an unexpected, strong and selective inhibitionof factor Xa, and this also applies to the compounds excluded bydisclaimer from the chemical product protection.

The present invention further provides medicaments and pharmaceuticalcompositions comprising at least one compound of the general formula (I)according to the invention together with one or more pharmacologicallyacceptable auxiliaries or excipients, which medicaments andpharmaceutical compositions can be used for the indications mentionedabove.

Furthermore, the present invention relates to a method for theprophylaxis and/or treatment of disorders of the human or animal body,in particular of the abovementioned disorders, using the compounds ofthe general formula (I) according to the invention—including thecompounds excluded by disclaimer from the chemical product protection.

Furthermore, the present invention also includes a method for preventingblood coagulation in vitro, in particular in banked blood or biologicalsamples which contain factor Xa, which method is characterized in thatcompounds of the general formula (I)—including the compounds excluded bydisclaimer from the chemical product protection—are added.

All customary administration forms are suitable for administration ofthe compounds according to the invention. Administration is preferablycarried out orally, lingually, sublingually, buccally, rectally orparenterally (i.e. bypassing the intestinal tract, that isintravenously, intraarterially, intracardially, intracutaneously,subcutaneously, transdermally, intraperitoneally or intramuscularly).Particularly suitable are oral and intravenous administration. Veryparticular preference is given to oral administration, this being afurther advantage with respect to the prior-art therapy ofthromboembolic disorders.

The novel active compounds of the general formula (I) can be convertedin a known manner into the customary formulations, such as tablets,sugar-coated tablets, pills, granules, aerosols, syrups, emulsions,suspensions and solutions, using inert non-toxic pharmaceuticallysuitable excipients or solvents. Here, the therapeutically activecompound should in each case be present in a concentration of from about0.1 to 95% by weight, preferably from 0.5 to 90% by weight, inparticular from 1 to 85% by weight, of the total mixture, i.e. inamounts which are sufficient in order to achieve the dosage rangeindicated.

In spite of this, if appropriate, it may be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on the individual response to the medicament, onthe manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual administrations over the course ofthe day.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example if thediluent used is water, optionally to use organic solvents as auxiliarysolvents.

In general it has proved advantageous in the case of intravenousadministration to administer amounts from approximately 0.001 to 10mg/kg, preferably approximately 0.01 to 10 mg/kg, in particularapproximately 0.1 to 8 mg/kg, of body weight to achieve effectiveresults.

In general, it has proved advantageous in the case of oraladministration to administer amounts from approximately 0.01 to 50mg/kg, preferably approximately 0.1 to 10 mg/kg, in particularapproximately 0.5 to 8 mg/kg, of body weight to achieve effectiveresults.

In spite of this, if appropriate, it may be necessary in the case ofintravenous or oral administration to depart from the amounts mentioned,namely depending on the body weight or on the type of administrationroute, on the individual response to the medicament, on the manner ofits formulation and the time or interval at which administration takesplace. Thus, in some cases it may be adequate to manage with less thanthe abovementioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of the administration ofrelatively large amounts, it may be advisable to divide these over thecourse of the day, namely into several individual doses or as acontinuous infusion.

Compared to the conventional preparations for treating thromboembolicdisorders, the compounds of the general formula (I) according to theinvention—including the compounds excluded by disclaimer from thechemical product protection—are distinguished in particular by the factthat a greater therapeutic range is achieved by the selective inhibitionof factor Xa. For the patient, this means a lower risk of, bleeding, andfor the treating physician, this means that the patient is easier toadjust. Moreover—owing to the mechanism—the onset of action is morerapid. Above all, however, the compounds according to the inventionpermit an oral administration form, which is a further advantage of thetherapy with the compounds according to the invention.

The present invention is illustrated by the examples below; however,these examples are not meant to restrict the invention in any way.

EXAMPLES

A Evaluation of the Physiological Activity

1. General Test Methods

The particularly advantageous biological properties of the compoundsaccording to the invention can be determined by the following methods.

a) Test Description (In Vitro)

a.1) Determination of the Factor Xa Inhibition

The enzymatic activity of human factor Xa (FXa) was measured using theconversion of a chromogenic substrate specific for FXa. Factor Xacleaves p-nitroaniline from the chromogenic substrate. Thedeterminations were carried out in microtitre plates as follows.

The test substances, in various concentrations, were dissolved in DMSOand incubated at 25° C. with human FXa (0.5 nmol/l dissolved in 50mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)-aminomethane], 150mmol/l of NaCl, 0.1% BSA (bovine serum albumin), pH=8.3) for 10 minutes.Pure DMSO was used as control. The chromogenic substrate (150 μmol/l ofPefachrome® FXa from Pentapharm) was then added. After an incubationtime of 20 minutes at 25° C., the extinction at 405 nm was determined.The extinctions of the test mixtures containing test substance werecompared with the control mixtures without test substance, and the IC₅₀values were calculated from these data.

a.2) Determination of the Selectivity

To assess selective FXa inhibition, the test substances were examinedfor their inhibition of other human serine proteases such as thrombin,trypsin and plasmin. To determine the enzymatic activity of thrombin (75mU/ml), trypsin (500 mU/ml) and plasmin (3.2 mmol/l), these enzymes weredissolved in tris buffer (100 mmol/l, 20 mmol/l CaCl₂, pH=8.0) andincubated with test substance or solvent for 10 minutes. The enzymaticreaction was then started by adding the corresponding specificchromogenic substrates (Chromozym Thrombin® from Boehringer Mannheim,Chromozym Trypsin® from Boehringer Mannheim, Chromozym Plasmin® fromBoehringer Mannheim) and the extinction at 405 nm was determined after20 minutes. All determinations were carried out at 37° C. Theextinctions of the test mixtures containing test substance were comparedwith the control samples without test substance, and the IC₅₀ valueswere calculated from these data.

a.3) Determination of the Anticoagulant Action

The anticoagulant action of the test substances was determined in vitroin human plasma. To this end, human blood was drawn off in a mixingratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citratesolution as receiver. Immediately after the blood had been drawn off, itwas mixed thoroughly and centrifuged at about 2000 g for 10 minutes. Thesupernatant was pipetted off. The prothrombin time (PT, synonyms:thromboplastin time, quick test) was determined in the presence ofvarying concentrations of test substance or the corresponding solventusing a commercial test kit (Neoplastin® from Boehringer Mannheim). Thetest compounds were incubated with the plasma at 37° C. for 10 minutes.Coagulation was then started by addition of thromboplastin, and the timewhen coagulation occurred was determined. The concentration of testsubstance which effected a doubling of the prothrombin time wasdetermined.

b) Determination of the Antithrombotic Activity (In Vivo)

b.1) Arteriovenous Shunt Model (Rat)

Fasting male rats (strain: HSD CPB:WU) having a weight of 200–250 g wereanaesthetized using a Rompun/Ketavet solution (12 mg/kg/ 50 mg/kg).Thrombus formation was initiated in an arteriovenous shunt in accordancewith the method described by Christopher N. Berry et al., Br. J.Pharmacol. (1994), 113, 1209–1214. To this end, the left jugular veinand the right carotid artery were exposed. The two vessels wereconnected by an extracorporeal shunt using a polyethylene tube (PE 60)of a length of 10 cm. In the middle, this polyethylene tube was attachedto a further polyethylene tube (PE 160) of a length of 3 cm whichcontained a roughened nylon thread which had been arranged to form aloop, to form a thrombogenic surface. The extracorporeal circulation wasmaintained for 15 minutes. The shunt was then removed and the nylonthread with the thrombus was weighed immediately. The weight of thenylon thread on its own had been determined before the experiment wasstarted. Before the extracorporeal circulation was set up, the testsubstances were administered to the animals while awake eitherintravenously via the tail vein or orally using a pharyngeal tube.

The results are shown in Table 1:

TABLE 1 Antithrombotic activity in the arteriovenous shunt model (rat)after oral or intravenous administration Example ED₅₀ [mg/kg]p.o. ED₅₀[mg/kg]i.v. 1 10 17 6 44 3 95 3 114 3 115 3 123 3 162 3b.2) Arteriel Thrombosis Model (Rat)

Male fasting rats (strain: HSD CPB: WU) were anaesthetized as describedabove. On average, the rats had a weight of about 200 g. The leftcarotid artery was exposed (about 2 cm). The formation of an arterialthrombus was induced by mechanical injury to the blood vessel inaccordance with the method described by K. Meng et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115–119. To thisend, the exposed carotid artery was clamped from the blood flow, cooledto −12° C. in a metal trough for 2 minutes and, to standardize the sizeof the thrombi, simultaneously compressed using a weight of 200 g. Theblood flow was then additionally reduced by a clip which was placedaround the carotid artery distally from the injured section of thevessel. The proximal clamp was removed, and the wound was closed andre-opened after 4 hours to remove the injured section of the vessel. Thesection of the vessel was opened longitudinally and the thrombus wasremoved from the injured section of the vessel. The moist weight of thethrombi was determined immediately. The test substances wereadministered to the animals while awake at the beginning of theexperiment, either intravenously via the tail vein or orally using apharyngeal tube.

b.3) Venous Thrombosis Model (Rat)

Male fasting rats (strain: HSD CPB: WU) were anaesthetized as describedabove. On average, the rats had a weight of about 200 g. The leftjugular vein was exposed (about 2 cm). The formation of a venousthrombus was induced by mechanical injury to the blood vessel inaccordance with the method described by K. Meng, et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115–119. To thisend, the jugular vein was clamped from the blood flow, cooled to −12° C.in a metal trough for 2 minutes and, to standardize the size of thethrombi, simultaneously compressed using a weight of 200 g. The bloodflow was re-opened and the wound was closed. After 4 hours, the woundwas re-opened to remove the thrombi from the injured sections of thevessel. The moist weight of the thrombi was determined immediately. Thetest substances were administered to the animals while awake at thebeginning of the experiment, either intravenously via the tail vein ororally using a pharyngeal tube.

B Preparation Examples

Starting Materials

The preparation of 3-morpholinone is described in U.S. Pat. No.5,349,045.

The preparation of N-(2,3-epoxypropyl)phthalimide is described in J.-W.Chern et al. Tetrahedron Lett. 1998,39,8483.

The substituted anilines can be obtained by reacting, for example,4-fluoronitrobenzene, 2,4-difluoronitrobenzene or 4-chloronitrobenzenewith the appropriate amines or amides in the presence of a base. Thiscan also be carried out using Pd catalysts, such asPd(OAc)₂/DPPF/NaOt-Bu (Tetrahedron Lett. 1999,40,2035) or copper(Renger, Synthesis 1985,856; Aebischer et al., Heterocycles1998,48,2225). Likewise, it is possible to initially convert halogenatedaromatics without nitro group into the corresponding amides, followed bynitration in the 4-position (U.S. Pat. No. 3,279,880).

I. 4-(4-Morpholin-3-onyl)nitrobenzene

2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79,1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NNP). Over aperiod of 2 h, 88 g (2.2 mol) of sodium hydride (60% in paraffin) arethen added a little at a time. After the evolution of hydrogen hasceased, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise withcooling at room temperature, over a period of 1 h, and the reactionmixture is then stirred overnight. At 12 mbar and 76° C., 1.71 l of theliquid volume are then distilled off, the residue is poured into 2 l ofwater and this mixture is extracted twice with in each case 1 l of ethylacetate. After washing of the combined organic phases with water, themixture is dried over sodium sulphate and the solvent is distilled offunder reduced pressure. Purification is carried out by silica gelchromatography using hexane/ethyl acetate (1:1) and subsequentcrystallization from ethyl acetate. This gives 78 g of product as acolourless to brownish solid, in a yield of 17.6% of theory.

¹H-NMR (300 MHz, CDCl₃): 3.86 (m, 2 H, CH₂CH₂), 4.08 (m, 2 H, CH₂CH₂),4.49 (s, 2H, CH₂CO), 7.61 (d, 2 H, ³J=8.95 Hz, CHCH), 8.28 (d, 2H,³J=8.95 Hz, CHCH) MS (r.I. %)=222 (74, M^(+.)), 193 (100), 164 (28), 150(21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25)

The following compounds were synthesized analogously:

-   -   3-fluoro4-(4-morpholin-3-onyl)nitrobenzene    -   4-(N-piperidonyl)nitrobenzene    -   3-fluoro-4-(N-piperidonyl)nitrobenzene    -   4(N-pyrrolidonyl)nitrobenzene    -   3-fluoro4-(N-pyrrolidonyl)nitrobenzene

II. 4-(4-Morpholin-3-onyl)aniline

In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzeneare dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C(5% ig) and hydrogenated at 70° C. and a hydrogen pressure of 50 bar for8 h. The catalyst is filtered off, the solvent is then distilled offunder reduced pressure and the product is purified by crystallizationfrom ethyl acetate. 20 g of product are obtained as a colourless tobluish solid, in a yield of 37.6% of theory.

Purification can also be carried out by silica gel chromatography usinghexane/ethyl acetate.

¹H-NMR (300 MHz, CDCl₃): 3.67 (m, 2 H, CH₂CH₂), 3.99 (m, 2 H, CH₂CH₂),4.27 (s, 2 H, CH₂CO), 6.68 (d, 2 H, ³J=8.71 Hz, CHCH), 7.03 (d, 2 H,³J=8.71 Hz, CHCH) MS (r.I. %)=192 (100, M^(+.)), 163 (48), 133 (26), 119(76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)

The following compounds were synthesized analogously:

-   -   3-fluoro4-(4-morpholin-3-onyl)aniline    -   4-(N-piperidonyl)aniline    -   3-fluoro4-(N-piperidonyl)aniline    -   4-(N-pyrrolidonyl)aniline    -   3-fluoro4(N-pyrrolidonyl)aniline        General Method for Preparing 4-substituted Anilines by Reacting        1-fluoro-4-nitrobenzenes and 1-chloro-4-nitrobenzenes with        Primary or Secondary Amines, Followed by Reduction

Equimolar amounts of the fluoronitrobenzene or chloronitrobenzene andthe amine are dissolved in dimethyl sulphoxide or acetonitrile (0.1 M to1 M solution), and the mixture is stirred at 100° C. overnight. Aftercooling to RT, the reaction mixture is diluted with ether and washedwith water. The organic phase is dried over MgSO₄, filtered andconcentrated. If a precipitate forms in the reaction mixture, theprecipitate is filtered off and washed with ether or acetonitrile. Ifthe mother liquor also contains product, it is worked up as describedusing ether and water. The crude products can be purified by silica gelchromatography (dichloromethane/cyclohexane and dichloromethane/ethanolmixtures).

For the subsequent reduction, the nitro compound is dissolved inmethanol, ethanol or ethanol/dichloromethane mixtures (0.01 M to 0.5 Msolution) admixed with palladium on carbon (10%) and stirred under anatmospheric hydrogen pressure overnight. The mixture is then filteredand concentrated. The crude product can be purified by silica gelchromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

Alternatively, the reducing agent used can also be iron powder. To thisend, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 Msolution) and, at 90° C., six equivalents of iron powder and water (0.3to 0.5 times the volume of the acetic acid) are added a little at a timeover a period of 10–15 min. After a further 30 min at 90° C., themixture is filtered and the filtrate is concentrated. The residue isworked up by extraction with ethyl acetate and 2N aqueous sodiumhydroxide solution. The organic phase is dried over magnesium sulphate,filtered and concentrated. The crude product can be purified by silicagel chromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

The following starting materials were prepared in an analogous manner:

III-1. tert-butyl-1-(4-aminophenyl)-L-prolinate

MS (ESI): m/z (%)=304 (M+H+MeCN, 100), 263 (M+H, 20); HPLC (method 4):rt=2.79 min.

III-2. 1-(4-aminophenyl)-3-piperidinecarboxamide

MS (ESI): m/z (%)=220 (M+H, 100); HPLC (method 4): rt=0.59 min.

III-3. 1-(4-aminophenyl)-4-piperidincarboxamide

MS (ESI): m/z (%)=220 (M+H, 100); HPLC (method 4): rt=0.57 min.

III-4. 1-(4-aminophenyl)-4-piperidinone

MS (ESI): m/z (%)=191 (M+H, 100); HPLC (method 4): rt=0.64 min.

III-5. 1-(4-aminophenyl)-L-prolinamide

MS (ESI): m/z (%)=206 (M+H, 100); HPLC (method 4): rt=0.72 min.

III-6. [1-(4-aminophenyl)-3-piperidinyl]methanol

MS (ESI): m/z (%)=207 (M+H, 100); HPLC (method 4): rt=0.60 min.

III-7. [1-(4-aminophenyl)-2-piperidinyl]methanol

MS (ESI): m/z (%)=207 (M+H, 100); HPLC (method 4): rt=0.59 min.

III-8. ethyl 1-(4-aminophenyl)-2-piperidinecarboxylate

MS (ESI): m/z (%)=249 (M+H, 35), 175 (100); HPLC (method 4): rt=2.43min.

III-9. [1-(4-aminophenyl)-2-pyrrolidinyl]methanol

MS (ESI): m/z (%)=193 (M+H, 45); HPLC (method 4): rt=0.79 min.

III-10. 4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenylamine

starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazole (Ziegler,Carl B., et al.; J. Heterocycl. Chem.; 25; 2; 1988; 719–723)

MS (ESI): m/z (%)=220 (M+H, 50), 171 (100); HPLC (method 4): rt=0.54min.

III-11. 4-(1-pyrrolidinyl)-3-(trifluoromethyl)aniline

MS (ESI): m/z (%)=231 (M+H, 100); HPLC (method 7): rt=3.40 min.

III-12. 3-chloro-4-(1-Pyrrolidinyl)aniline

MS (ESI): m/z (%)=197 (M+H, 100); HPLC (method 4): rt=0.78 min.

III.-13. 5-amino-2-(4-morpholinyl)benzamide

MS (ESI): m/z (%)=222 (M+H, 100); HPLC (method 4): rt=0.77 min.

III-14. 3-methoxy-4-(4-morpholinyl)aniline

MS (ESI): m/z (%)=209 (M+H, 100); HPLC (method 4): rt=0.67 min.

III-15. 1-[5-amino-2-(4-morpholinyl)phenyl]ethanone

MS (ESI): m/z (%)=221 (M+H, 100); HPLC (method 4): rt=0.77 min.

General Method for Preparing 4-substituted Anilines by Reacting1-fluoro4-nitrobenzenes with Amides, Followed by Reduction

The amide is dissolved in DMF and admixed with 1.5 equivalents ofpotassium tert-butoxide. The mixture is stirred at RT for 1 h, and 1.2equivalents of the 1-fluoro4-nitrobenzene are then added a little at atime. The reaction mixture is stirred at RT overnight, diluted withether or ethyl acetate and washed with sat. aqu. sodium bicarbonatesolution. The organic phase is dried over magnesium sulphate, filteredand concentrated. The crude product can be purified by silica gelchromatography (dichloromethane/ethanol mixtures).

For the subsequent reduction, the nitro compound is dissolved in ethanol(0.01 M to 0.5 M solution), admixed with palladium on carbon (10%) andstirred under atmospheric hydrogen pressure overnight. The mixture isthen filtered and concentrated. The crude product can be purified bysilica gel chromatography (dichloromethane/ethanol mixtures) orpreparative reversed-phase BPLC (acetonitrile/water mixtures).

Alternatively, the reducing agent used can also be iron powder. To thisend, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 Msolution) and, at 90° C., six equivalents of iron powder and water (0.3to 0.5 times the volume of the acetic acid) are added a little at a timeover a period of 10–15 min. After a further 30 min at 90° C., themixture is filtered and the filtrate is concentrated. The residue isworked up by extraction with ethyl acetate and 2N aqueous sodiumhydroxide solution. The organic phase is dried over magnesium sulphate,filtered and concentrated. The crude product can be purified by silicagel chromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

The following starting materials were prepared in an analogous manner:

IV-1. 1-[4-amino-2-(trifluoromethyl)phenyl]-2-pyrrolidinone

MS (ESI): m/z (%)=245 (M+H, 100); HPLC (method 4): rt=2.98 min

IV-2. 4-[4-amino-2-(trifluoromethyl)phenyl]-3-morpholinone

MS (ESI): m/z (%)=261 (M+H, 100); HPLC (method 4): rt=2.54 min.

IV-3. 4-(4-amino-2-chlorophenyl)-3-morpholinone

MS (ESI): m/z (%)=227 (M+H, 100); HPLC (method 4): rt=1.96 min.

IV-4. 4-(4-amino-2-methylphenyl)-3-morpholinone

MS (ESI): m/z (%)=207 (M+H, 100); HPLC (method 4): rt=0.71 min.

IV-5. 5-amino-2-(3-oxo-4-morpholinyl)benzonitrile

MS (ESI): m/z (%)=218 (M+H, 100); HPLC (method 4): rt=1.85 min.

IV-6. 1-(4-amino-2-chlorophenyl)-2-pyrrolidinone

MS (ESI): m/z (%)=211 (M+H, 100); HPLC (method 4): rt=2.27 min.

IV-7. 4-(4-amino-2,6-dimethylphenyl)-3-morpholinone

starting from 2-fluoro-1,3-dimethyl-5-nitrobenzene (Bartoli et al., J.Org. Chem. 1975, 40, 872):

MS (ESI): m/z (%)=221 (M+H, 100); HPLC (method 4): rt=0.77 min.

IV-8. 4-(2,4-diaminophenyl)-3-morpholinone

starting from 1-fluoro-2,4dinitrobenzene:

MS (ESI): m/z (%)=208 (M+H, 100); HPLC (method 4): rt=0.60 min.

IV-9. 4-(4-amino-2-chlorophenyl)-2-methyl-3-morpholinone

starting from 2-methyl-3-morpholinone (Pfeil, E.; Harder, U.; Angew.Chem. 1967, 79, 188):

MS (ESI): m/z (%)=241 (M+H, 100); HPLC (method 4): rt=2.27 min.

IV-10. 4-(4-amino-2-chlorophenyl)-6-methyl-3-morpholinone

starting from 6-methyl-3-morpholinone (EP 350 002):

MS (ESI): m/z (%)=241 (M+H, 100); HPLC (method 4): rt=2.43 min.

Synthesis Examples

The Examples 1 to 13, 17 to 19 and 36 to 57 below refer to processvariant [A].

Example 1 Preparation of5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

(5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one(preparation see S. J. Brickner et al., J. Med. Chem. 1996, 39, 673)(0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid (0.25 g, 1.52mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.3 g, 1.3equivalents) are dissolved in 9.9 ml of DMF. 0.31 g (1.98 mmol, 1.3equivalents) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) areadded, and 0.39 g (0.53 ml, 3.05 mmol, 2 equivalents) ofdiisopropylethylamine (DIEA) are added dropwise at room temperature. Themixture is stirred at room temperature overnight. 2 g of silica gel areadded, and the mixture is evaporated to dryness under reduced pressure.The residue is chromatographed on silica gel using a toluene/ethylacetate gradient. This gives 0.412 g (61.5% of theory) of the targetcompound of melting point (m.p.) 197° C.

R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.29 (starting material=0.0); MS(DCI) 440.2 (M+H), Cl pattern; ¹H-NMR (d₆-DMSO, 300 MHz) 2.95 (m, 4H),3.6 (t, 2H), 3.72 (m, 4H), 3.8 (dd, 1H), 4.12 (t, 1H), 4.75–4.85 (m,1H), 7.05 (t, 1H), 7.15–7.2 (m, 3H), 7.45 (dd, 1H), 7.68 (d, 1H), 8.95(t, 1H).

Example 25-Chloro-N-{[(5S)-3-(4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

is obtained analogously from benzyl 4-morpholinophenylcarbamate via the(5S)-5-(aminomethyl)-3-(4-morpholinophenyl)-1,3-oxazolidin-2-oneintermediate (see Example 1).

M.p.: 198° C.; IC₅₀ value=43 nM; R_(f) (SiO₂, toluene/ethyl acetate1:1)=0.24.

Example 35-Chloro-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-1,3-oxazolidin-2-one(preparation see M. R. Barbachyn et al., J. Med. Chem. 1996, 39, 680).

M.p.: 193° C.; Yield: 82%; R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.47(starting material=0.0).

Example 4 5-Bromo-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

is obtained analogously from 5-bromothiophene-2-carboxylic acid.

M.p.: 200° C.

Example 5N-({(5S)-3-[3-Fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-methyl-2-thiophenecarboxamide

is obtained analogously from 5-methylthiophene-2-carboxylic acid.

M.p.: 167° C.

Example 65-Chloro-N-{[(5S)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

is obtained analogously from(5S)-5-(aminomethyl)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-1,3-oxazolidin-2-one(preparation see EP-A-785 200).

M.p.: 247° C.

Example 75-Chloro-N-{[(5S)-3-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

is obtained analogously from6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-methyl-1,3-benzothiazol-2(3H)-one(preparation see EP-A-738 726).

M.p.: 217° C.

Example 85-Chloro-N-[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

is obtained analogously from(5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-1,3-oxazolidin-2-one(preparation analogously to J. A. Tucker et al., J. Med. Chem. 1998, 41,3727).

MS (ESI) 516 (M+H), Cl pattern.

Example 95-Chloro-N-({(5S)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-1,3-oxazolidin-2-one.

Example 105-Chloro-N-({(5S)-3-[3-fluoro-4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxy-carbonylpiperazin-1-yl)phenyl]-1,3-oxazolidin-2-one(preparation see WO-A-93/23384, which has already been cited).

M.p.: 184° C.; R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.42.

Example 115-Chloro-N-({(5S)-3-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

is obtained by reacting Example 10 with trifluoroacetic acid inmethylene chloride.

IC₅₀ value=140 nM;

¹H-NMR [d₆-DMSO]: 3.01–3.25 (m, 8H), 3.5–3.65 (m, 2H), 3.7–3.9 (m, 1H),4.05–4.2 (m, 1H), 4.75–4.9 (m, 1H), 7.05–7.25 (m, 3H), 7.5 (dd, 1H), 7.7(d, 1H), 8.4 (broad s, 1H), 9.0 (t, 1H).

Example 125-Chloro-N-[((5S)-3-(2,4′-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

is obtained analogously from(5S)-5-aminomethyl-3-(2,4-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-2-one(preparation see EP-A-789 026).

R_(f) (SiO₂, ethyl acetate/ethanol 1:2)=0.6; MS (ESI) 515 (M+H), Clpattern.

Example 135-Chloro-N-{[(5S)-2-oxo-3-(4-piperidinophenyl)-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

is obtained from5-(hydroxymethyl)-3-(4-piperidinophenyl)-1,3-oxazolidin-2-one(preparation see DE 2708236) after mesylation, reaction with potassiumphthalimide, hydrazinolysis and reaction with5-chlorothiophene-2-carboxylic acid.

R_(f) (SiO₂, ethyl acetate/toluene 1:1)=0.31; m.p. 205° C.

Example 175-Chloro-N-({(5S)-2-oxo-3-[4-(2oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Analogously to the known synthesis scheme (see S. J. Brickner et al., J.Med. Chem. 1996, 39, 673), 1-(4-aminophenyl)pyrrolidin-2-one(preparation see Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955;209) gives, after reaction with benzyloxycarbonyl chloride, followed byreaction with R-glycidyl butyrate, mesylation, reaction with potassiumphthalimide, hydrazinolysis in methanol and reaction with5-chlorothiophene-2-carboxylic acid, finally5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thio-phenecarboxamide. The5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)-phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamideobtained in this manner has an IC₅₀ value of 4 nM (test method for theIC₅₀ value according to Example A-1.a.1 described above) “determinationof the inhibition of factor Xa”).

M.p.: 229° C.; R_(f) value (SiO₂, toluene/ethyl acetate 1:1)=0.05(starting material:=0.0); MS (ESI): 442.0 (21%, M+Na, Cl pattern), 420.0(72%, M+H, Cl pattern), 302.3 (12%), 215(52%), 145 (100%); ¹H-NMR(d₆-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H), 3.77–3.85(m,3H), 4.15(t,1H), 4.75–4.85 (m,1H), 7.2 (d,1H), 7.5 (d,2H), 7.65(d,2H), 7.69 (d,1H), 8.96 (t,1H).

The individual steps of the synthesis of Example 17 described above withthe respective precursors are as follows:

At −20° C., 4 g (22.7 mmol) of 1-(4-aminophenyl)pyrrolidin-2-one and 3.6ml (28.4 mmol) of N,N-dimethylaniline in 107 ml of tetrahydrofuran areadmixed slowly with 4.27 g (25.03 mmol) of benzyl chloroformate. Themixture is stirred at −20° C. for 30 minutes and then allowed to warm toroom temperature. 0.5 l of ethyl acetate are added, and the organicphase is washed with 0.5 l of saturated NaCl solution. The organic phaseis separated off and dried with MgSO₄, and the solvent is evaporatedunder reduced pressure. The residue is triturated with diethyl ether andfiltered off with suction. This gives 5.2 g (73.8% of theory) of benzyl4-(2-oxo-1-pyrrolidinyl)phenylcarbamate as light-beige crystals ofmelting point 174° C.

At −10° C. and under argon, 1.47 g (16.66 mmol) of isoamyl alcohol in200 ml of tetrahydrofuran are admixed dropwise with 7.27 ml of a 2.5 Msolution of n-butyllithium (BuLi) in hexane, a further 8 ml of BuLisolution being required for the added indicator N-benzylidenebenzylamineto change colour. The mixture is stirred at −10° C. for 10 minutes andcooled to −78° C., and a solution of 4.7 g (15.14 mmol) of benzyl4-(2-oxo-1-pyrrolidinyl)phenylcarbamate is added slowly. Another 4 ml ofn-BuLi solution are then added until the colour of the indicator changesto pink. The mixture is stirred at −78° C. for 10 minutes, 2.62 g (18.17mmol) of R-glycidyl butyrate are added and the mixture is stirred at−78° C. for another 30 minutes.

Overnight, the mixture is allowed to warm to room temperature, 200 ml ofwater are added and the THF fraction is evaporated under reducedpressure. The aqueous residue is extracted with ethyl acetate and theorganic phase is dried with MgSO₄ and evaporated under reduced pressure.The residue is triturated with 500 ml of diethyl ether and theprecipitated crystals are filtered off with suction under reducedpressure.

This gives 3.76 g (90% of theory) of(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneof melting point 148° C., with an R_(f) value (SiO₂, toluene/ethylacetate 1:1) of 0.04 (starting material=0.3).

At 0° C., 3.6 g (13.03 mmol) of(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneand 2.9 g (28.67 mmol) of triethylamine are initially charged withstirring in 160 ml of dichloromethane. 1.79 g (15.64 mmol) ofmethanesulphonyl chloride are added with stirring, and the mixture isstirred at 0° C. for 1.5 hours and then at room temperature for 3 h.

The reaction mixture is washed with water and the aqueous phase isreextracted with methylene chloride. The combined organic extracts aredried with MgSO₄ and concentrated. The residue (1.67 g) is thendissolved in 70 ml of acetonitrile, admixed with 2.62 g (14.16 mmol) ofpotassium phthalimide and stirred in a closed vessel at 180° C. in amicrowave oven for 45 minutes.

The mixture is filtered off from insoluble residues, the filtrate isevaporated under reduced pressure and the residue (1.9 g) is dissolvedin methanol and admixed with 0.47 g (9.37 mmol) of hydrazine hydrate.The mixture is boiled for 2 hours, cooled, admixed with saturated sodiumbicarbonate solution and extracted six times with a total of 2 l ofmethylene chloride. The combined organic extracts of the crude(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneare dried with MgSO₄ and concentrated under reduced pressure.

The end product,5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide,is prepared by dissolving 0.32 g (1.16 mmol) of the(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneprepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g; 1.16 mmol)and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.23 g, 1.51 mmol) in 7.6ml of DMF. 0.29 g (1.51 mmol) ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) are added, and 0.3g (0.4 ml; 2.32 mmol, 2 equivalents) of diisopropylethylamine (DIEA) areadded dropwise at room temperature. The mixture is stirred at roomtemperature overnight.

The mixture is evaporated to dryness under reduced pressure and theresidue is dissolved in 3 ml of DMSO and chromatographed on an RP-MPLCusing an acetonitrile/water/0.5% TFA gradient. From the appropriatefractions, the acetonitrile fraction is evaporated and the precipitatedcompound is filtered off with suction. This gives 0.19 g (39% of theory)of the target compound.

The following compounds were prepared in an analogous manner:

Example 185-Chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Analogously to Example 17, 4-pyrrolidin-1-yl-aniline (Reppe et al.,Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the compound5chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

IC₅₀=40 nM; m.p.: 216° C.; R_(f) value (SiO₂, toluene/ethyl acetate1:1)=0.31 [starting material:=0.0].

Example 195-Chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Analogously, N,N-diethylphenyl-1,4-diamine (U.S. Pat. No. 2,811,555;1955) gives the compound5-chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

IC₅₀=270 nM; m.p.: 181° C.; R_(f) value (SiO₂, toluene/ethyl acetate1:1)=0.25 [starting material:=0.0].

Example 365-Chloro-N-({(5S)-3-[2-methyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

starting from 2-methyl4-(4-morpholinyl)aniline (J. E. LuValle et al. J.Am. Chem. Soc. 1948, 70, 2223):

MS (ESI): m/z (%)=436 ([M+H]⁺, 100), Cl pattern; HPLC (method 1): rt(%)=3.77 (98). IC₅₀: 1.26 μM

Example 375-Chloro-N-{[(5S)-3-(3-chloro-4-morpholinophenyl)-2-oxo-1,3oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

starting from 3-chloro4(4-morpholinyl)aniline (H. R. Snyder et al. J.Pharm. Sci. 1977, 66, 1204):

MS (ESI): m/z (%)=456 ([M+H]⁺, 100), Cl₂ pattern; HPLC (method 2): rt(%)=4.31 (100). IC₅₀: 33 nM

Example 385-Chloro-N-({(5S)-3-[4-(4-morpholinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

starting from 4-(4-morpholinylsulphonyl)aniline (Adams et al. J. Am.Chem. Soc. 1939, 61, 2342):

MS (ESI): m/z (%)=486 ([M+H]⁺, 100), Cl pattern; HPLC (method 3): rt(%)=4.07 (100). IC₅₀: 2 μM

Example 395-Chloro-N-({(5S)-3-[4-(1-azetidinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

starting from 4-(1-azetidinylsulphonyl)aniline:

MS (DCI, NH₃): m/z (%)=473 ([M+NH]⁺, 100), Cl pattern; HPLC (method 3):rt (%)=4.10 (100). IC₅₀: 0.84 μM

Example 405-Chloro-N-[((5S)-3-{4-[(dimethylamino)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

starting from 4-amino-N,N-dimethylbenzenesulphonamide (I. K. Khanna etal. J. Med. Chem. 1997,40, 1619):

MS (ESI): m/z (%)=444 ([M+H]⁺, 100), Cl pattern; HPLC (method 3): rt(%)=4.22 (100). IC₅₀: 90 nM

General Method for the Acylation of5-(aminomethyl)-3-[4-(2-oxo-1-pyrro-lidinyl)phenyl]-1,3-oxazolidin-2-onewith Carbonyl Chlorides.

Under argon and at room temperature, an about 0.1 molar solution of5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one(from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) inabsolute dichloromethane is added dropwise to the appropriate acidchloride (2.5 eq.). The mixture is stirred at room temperature for about4 h, and about 5.5 eq of PS-trisamine (Argonaut Technologies) are thenadded. The suspension is stirred gently for 2 h, diluted withdichloromethane/DMF (3:1) and then filtered (the resin is washed withdichloromethane/DMF) and the filtrate is concentrated. If appropriate,the product that is obtained is purified by preparative RP-HPLC.

The following compounds were prepared in an analogous manner:

Example 41N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide

LC-MS (method 6): m/z (%)=386 (M+H, 100); LC-MS: rt (%)=3.04 (100).IC₅₀: 1.3 μM

General Method for Preparing Acyl Derivatives Starting from5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneand Carboxylic Acids

The appropriate carboxylic acid (about 2 eq.) and a mixture of absolutedichloromethane/DMF (about 9:1) are added to 2.9 eq. of resin-bondedcarbodiimide (PS-carbodiimide, Argonaut Technologies). The mixture isshaken gently at room temperature for about 15 min,5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one(from Example 45) (1.0 eq.) is then added and the mixture is shakenovernight, after which the resin is filtered off (and washed withdichloromethane), and the filtrate is concentrated. If appropriate, theresulting product is purified by preparative RP-HPLC.

The following compounds were prepared in an analogous manner:

Example 425-Methyl-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

LC-MS: m/z (%)=400 (M+H, 100); LC-MS (method 6): rt (%)=3.23 (100).IC₅₀: 0.16 μM

Example 435-Bromo-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

LC-MS: m/z (%)=466 (M+H, 100); LC-MS (method 5): rt (%)=3.48 (78). IC₅₀:0.014 μM

Example 445-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-13oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

a)2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione:

A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A.Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water(9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, aftersome time again formation of a precipitate). The precipitate (desiredproduct) is filtered off, washed three times with diethyl ether anddried. The combined mother liquors are concentrated under reducedpressure and, after addition of a second portion of2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h(the precipitate dissolves, after some time again formation of aprecipitate). The precipitate (desired product) is filtered off, washedthree times with diethyl ether and dried. Total yield: 10.14 g, 92% oftheory.

MS (ESI): m/z (%)=418 ([M+Na]⁺, 84), 396 ([M+H]⁺, 93); HPLC (method 3):rt (%)=3.34 (100).

b)2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione:

Under argon and at room temperature, N,N′-carbonyldiimidazole (2.94 g,18.1 mmol) and dimethylaminopyridine (a catalytic amount) are added to asuspension of the amino alcohol (3.58 g, 9.05 mmol) in tetrahydrofuran(90 ml). The reaction suspension is stirred at 60° C. for 12 h (theprecipitate dissolves, after some time again formation of aprecipitate), admixed with a second portion of N,N′-carbonyldiimidazole(2.94 g, 18.1 mmol) and stirred at 60° C. for another 12 h. Theprecipitate (desired product) is filtered off, washed withtetrahydrofuran and dried. The filtrate is concentrated under reducedpressure and further product is purified by flash chromatography(dichloromethane/methanol mixtures). Total yield: 3.32 g, 87% of theory.

MS (ESI): m/z (%)=422 ([M+H]⁺, 100); HPLC (method 4): rt (%)=3.37 (100).

c)5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide:

At room temperature, methylamine (40% strength in water, 10.2 ml, 0.142mol) is added dropwise to a suspension of the oxazolidinone (4.45 g,10.6 mmol) in ethanol (102 ml). The reaction mixture is refluxed for 1 hand concentrated under reduced pressure. The crude product is usedwithout further purification for the next reaction.

Under argon and at 0° C., 5-chlorothiophene-2-carbonyl chloride (2.29 g,12.7 mmol) is added dropwise to a solution of the amine in pyridine (90ml). Ice-cooling is removed and the reaction mixture is stirred at roomtemperature for 1 h and admixed with water. Dichloromethane is added andthe phases are separated, and the aqueous phase is then extracted withdichloromethane. The combined organic phases are dried (sodiumsulphate), filtered and concentrated under reduced pressure. The desiredproduct is purified by flash chromatography (dichloromethane/methanolmixtures).

Total yield: 3.92 g, 86% of theory. M.p: 232–233° C.; ¹H NMR (DMSO-d⁶,200 MHz): 9.05–8.90 (t, J=5.8 Hz, 1H), 7.70 (d, J=4.1 Hz, 1H), 7.56 (d,J=9.0 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 7.20 (d, J=4.1 Hz, 1H), 4.93–4.75(m, 1H), 4.27–4.12 (m, 3H), 4.02–3.91 (m, 2H), 3.91–3.79 (dd, J=6.1 Hz,9.2 Hz, 1H), 3.76–3.66 (m, 2H), 3.66–3.54 (m, 2H); MS (ESI): m/z (%)=436([M+H]⁺, 100, Cl pattern); HPLC (method 2): rt (%)=3.60 (100); [α]²¹_(D)=−38° (c 0.2985, DMSO); ee: 99%. IC₅₀: 0.7 nM

The following compounds were prepared in an analogous manner:

Example 455-Methyl-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=831 ([2M+H]⁺, 100), 416 ([M+H]⁺, 66); HPLC (method 3):rt (%)=3.65 (100). IC₅₀: 4.2 nM

Example 465-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=480 ([M+H]⁺, 100, Br pattern); HPLC (method 3): rt(%)=3.87 (100). IC₅₀: 0.3 nM

Example 475-Chloro-N-{[(5S)-3-(3-isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

200 mg (0.61 mmol) of6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-onehydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran andadmixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol)of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture isstirred at room temperature overnight and then concentrated. The productis isolated by column chromatography (silica gel, methylenechloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory) of thedesired compound.

MS (ESI): m/z (%)=436 (M+H, 100); HPLC (method 4): rt=3.78 min.

The following compounds were prepared in an analogous manner;

Example No. Structure M.p. [° C.] IC₅₀ [μM] 48

210 0.12 49

234 0.074 50

195 1.15 51

212 1.19 52

160 0.19 53

MS (ESI):m/z (%) =431([M + H]⁺,100), Clpattern 0.74 54

221 0.13 from 5-amino-2-pyrrolidino-benzonitril (Grell, W., Hurnaus, R.,Griss, G., Sauter, R.; Rupprecht, E. et al.; J. Med. Chem. 1998, 41;5219) 55

256 0.04 from 3-(4-amino-phenyl)-oxazolidin-2-one (Artico, M. et al.;Farmaco Ed. Sci. 1969, 24; 179) 56

218 0.004 57

226 0.58 255

228–230

Examples 20 to 30 and 58 to 139 below refer to process variant [B], andExamples 20 and 21 describe the preparation of precursors.

Example 20 Preparation of N-allyl-5-chloro-2-thiophenecarboxamide

An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml ofabsolute pyridine and 14.2 ml of absolute THF is admixed dropwise with5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling isremoved and the mixture is stirred at room temperature for 3 h and thenconcentrated under reduced pressure. The residue is admixed with waterand the solid is filtered off. The crude product is purified by flashchromatography over silica gel (dichloromethane).

Yield: 7.20 g (99% of theory); MS (DCI, NH₄): m/z (%)=219 (M+NH₄, 100),202 (M+H, 32); HPLC (method 1): rt (%)=3.96 min (98.9).

Example 21 Preparation of5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

An ice-cooled solution of 2.0 g (9.92 mmol) ofN-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane isadmixed with meta-chloroperbenzoic acid (3.83 g, about 60% strength).The mixture is stirred overnight, during which it is allowed to warm toroom temperature, and is then washed with 10% sodium hydrogen sulphatesolution (three times). The organic phase is washed with saturatedsodium bicarbonate solution (twice) and with saturated sodium chloridesolution, dried over magnesium sulphate and concentrated. The product ispurified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).

Yield: 837 mg (39% of theory); MS (DCI, NH₄): m/z (%)=253 (M+NH₄, 100),218 (M+H, 80); HPLC (method 1): rt (%)=3.69 min (about 80).

General Method for Preparing SubstitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide DerivativesStarting from 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

At room temperature or at temperatures up to 80° C.,5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide (1.0 eq.) is addeda little at a time to a solution of the primary amine or anilinederivative (1.5 to 2.5 eq.) in 1,4-dioxane, 1,4-dioxane/water mixturesor ethanol, ethanol/water mixtures (about 0.3 to 1.0 mol/l). The mixtureis stirred for 2 to 6 hours and then concentrated. From the reactionmixture, the product can be isolated by silica gel chromatography(cyclohexane/ethyl acetate mixtures, dichloromethane/methanol mixturesor dichloromethane/methanol/triethylamine mixtures).

The following compounds were prepared in an analogous manner:

Example 22N-[3-(Benzylamino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=325 (M+H, 100); HPLC (method 1): rt (%)=3.87 min(97.9).

Example 235-Chloro-N-[3-(3-cyanoanilino)-2-hydroxypropyl]-2thiophenecarboxamide

MS (ESI): m/z (%)=336 (M+H, 100); HPLC (method 2): rt (%)=4.04 min(100).

Example 245-Chloro-N-[3-(4-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=336 (M+H, 100); HPLC (method 1): rt (%)=4.12 min(100).

Example 255-Chloro-N-{3-[4-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxamide

MS (ESI): m/z (%)=350 (M+H, 100); HPLC (method 4): rt (%)=3.60 min(95.4).

Example 265-Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxamide

MS (ESI): m/z (%)=350 (M+H, 100); HPLC (method 4): rt (%)=3.76 min(94.2).

Example 58 tert-Butyl4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-benzylcarbamate

starting from tert-butyl 4-aminobenzylcarbamate (Bioorg. Med. Chem.Lett.; 1997; 1921–1926):

MS (ES-pos): m/z (%)=440 (M+H, 100), (ES-neg): m/z (%)=438 (M−H, 100);HPLC (method 1): rt (%)=4.08 (100).

Example 59 tert-Butyl4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-phenyl-carbamate

starting from N-tert-butyloxycarbonyl-1,4-phenylenediamine:

MS (ESI): m/z (%)=426 (M+H, 45), 370 (100); HPLC (method 1): rt (%)=4.06(100).

Example 60 tert-Butyl2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)phenyl]amino}propyl-carbamate

starting from 1-(4-aminophenyl)-2-pyrrolidinone (Justus Liebigs Ann.Chem.; 1955; 596; 204):

MS (DCI, NH₃): m/z (%)=350 (M+H, 100); HPLC (method 1): rt (%)=3.57(97).

Example 615-Chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

800 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinone and 700mg (3.22 mmol) of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamidein 15 ml of ethanol and 1 ml of water are heated under reflux for 6hours. The mixture is concentrated under reduced pressure and treatedwith ethyl acetate, precipitated crystals are filtered off with suctionand the mother liquor is chromatographed giving 276 mg (17% of theory)of the target compound.

R_(f) (ethyl acetate): 0.25.

Example 62(N-(3-Anilino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

starting from aniline:

MS (DCI, NH₃): m/z (%)=311 ([M+H]⁺, 100), Cl pattern; HPLC (method 3):rt (%)=3.79 (100).

Example 635-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4morpholinyl)phenyl]amino}propyl)-2-thiophenecarboxamide

starting from 4-(4-aminophenyl)-3-morpholinone:

MS (ESI): m/z (%)=410 ([M+H]⁺, 50), Cl pattern; HPLC (method 3): rt(%)=3.58 (100).

Example 64N-[3-({4-[Acetyl(cyclopropyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

starting from N-(4-aminophenyl)-N-cyclopropylacetamide:

MS (ESI): m/z (%)=408 ([M+H]⁺, 100), Cl pattern; HPLC (method 3): rt(%)=3.77 (100).

Example 65N-[3-({4-[Acetyl(methyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

starting from N-(4-aminophenyl)-N-methylacetamide:

MS (ESI): m/z (%)=382 (M+H, 100); HPLC (method 4): rt=3.31 min.

Example 665-Chloro-N-(2-hydroxy-3-{[4-(1H-1,2,3-triazol-1-yl)phenyl]amino}propyl)-2-thiophenecarboxamide

starting from 4-(1H-1,2,3-triazol-1-yl)aniline (Bouchet et al.; J. Chem.Soc. Perkin Trans. 2; 1974; 449):

MS (ESI): m/z (%)=378 (M+H, 100); HPLC (method 4): rt=3.55 min.

Example 67 tert-butyl1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-L-prolinate

MS (ESI): m/z (%)=480 (M+H, 100); HPLC (method 4): rt=3.40 min.

Example 681-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]phenyl}-4-piperidinecarboxamide

MS (ESI): m/z (%)=437 (M+H, 100); HPLC (method 4): rt=2.39 min.

Example 691-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-3-piperidinecarboxamide

MS (ESI): m/z (%)=437 (M+H, 100); HPLC (method 4): rt=2.43 min.

Example 705-Chloro-N-(2-hydroxy-3-{[4-(4-oxo-1-piperidinyl)phenyl]amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=408 (M+H, 100); HPLC (method 4): rt=2.43 min.

Example 711-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]phenyl)-L-prolinamide

MS (ESI): m/z (%)=423 (M+H, 100); HPLC (method 4): rt=2.51 min.

Example 725-Chloro-N-[2-hydroxy-3-({4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-amino)propyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=424 (M+H, 100); HPLC (method 4): rt=2.43 min.

Example 735-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-amino)propyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=424 (M+H, 100); HPLC (method 4): rt=2.49 min.

Example 74 Ethyl1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-2-piperidinecarboxylate

MS (ESI): m/z (%)=466 (M+H, 100); HPLC (method 4): rt=3.02 min.

Example 755-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}amino)-propyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=410 (M+H, 100); HPLC (method 4): rt=2.48 min.

Example 765-Chloro-N-(2-hydroxy-3-{[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl]amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=437 (M+H, 100). HPLC (method 5): rt=1.74 min.

Example 775-Chloro-N-(2-hydroxy-3-{[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=448 (M+H, 100); HPLC (method 4): rt=3.30 min.

Example 785-Chloro-N-(2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=462 (M+H, 100); HPLC (method 4): rt=3.50 min.

Example 795-Chloro-N-(3-{[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxy-propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=444 (M+H, 100); HPLC (method 4): rt=3.26 min.

Example 805-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=478 (M+H, 100); HPLC (method 4): rt=3.37 min.

Example 815-Chloro-N-(2-hydroxy-3-{[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]amino}-propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=424 (M+H, 100); HPLC (method 4): rt=2.86 min.

Example 825-Chloro-N-(3-{[3-cyano4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=435 (M+H, 100); HPLC (method 4): rt=3.10 min.

Example 835-Chloro-N-(3-{[3-chloro-4-(1-pyrrolidinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=414 (M+H, 100); HPLC (method 4): rt=2.49 min.

Example 845-Chloro-N-(3-{[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=428 (M+H, 100); HPLC (method 4): rt=3.39 min.

Example 855-Chloro-N-(3-{[3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]amino)-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=438 (M+H, 100); HPLC (method 4): rt=2.84 min.

Example 86N-(3-{[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=439 (M+H, 100); HPLC (method 4): rt=2.32 min.

Example 875-Chloro-N-(2-hydroxy-3-{[3-methoxy-4-(4-morpholinyl)phenyl]amino}propyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=426 (M+H, 100); HPLC (method 4): rt=2.32 min.

Example 88N-(3-[3-Acetyl-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

MS (EST): m/z (%)=438 (M+H, 100); HPLC (method 4): rt=2.46 min.

Example 89N-(3-{[3-Amino-4-(3-oxo4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=425 (M+H, 100); HPLC (method 4): rt=2.45 min.

Example 905-Chloro-N-(3-{[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=458 (M+H, 100); HPLC (method 4): rt=3.44 min.

Example 915-Chloro-N-(3-{[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]amino)-2-hydroxypropyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=458 (M+H, 100); HPLC (method 4): rt=3.48 min.

Example 91a5-Chloro-N-[2-hydroxy-3-(14-[(3oxo4morpholinyl)methyl]phenyl}amino)-propyl]-2-thiophenecarboxamide

starting from 4-(4-amino-benzyl)-3-morpholinone (Surrey et al.; J. Amer.Chem. Soc.; 77; 1955; 633):

MS (ESI): m/z (%)=424 (M+H, 100); HPLC (method 4): rt=2.66 min.

General Method for Preparing 3-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamideDerivatives Starting from SubstitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide Derivatives

At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or a similarphosgene equivalent are added to a solution of the substitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide derivative(1.0 eq.) in absolute THF (about 0.1 mol/l). At room temperature or, ifappropriate, at elevated temperature (up to 70° C.), the mixture isstirred for 2 to 18 h and then concentrated under reduced pressure. Theproduct can be purified by silica gel chromatography(dichloromethane/methanol mixtures or cyclohexane/ethyl acetatemixtures).

The following compounds were prepared in an analogous manner:

Example 27N-[(3-Benzyl-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

MS (DCI, NH₄): m/z (%)=372 (M+Na, 100), 351 (M+H, 45); HPLC (method 1):rt (%)=4.33 min (100).

Example 285-Chloro-N-{[3-(3-cyanophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

MS (DCI, NH₄): m/z (%)=362 (M+H, 42), 145 (100); HPLC (method 2): rt(%)=4.13 min (100).

Example 295-Chloro-N-({3-[4-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=376 (M+H, 100); HPLC (method 4): rt=4.12 min

Example 305-Chloro-N-({3-[3-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=376 (M+H, 100); HPLC (method 4): rt=4.17 min

Example 92 tert-Butyl4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]benzylcarbamate

starting from Example 58:

MS (ESI): m/z (%)=488 (M+Na, 23), 349 (100); HPLC (method 1): rt(%)=4.51 (98.5).

Example 93 tert-Butyl4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenylcarbamate

starting from Example 59:

MS (ESI): m/z (%)=493 (M+Na, 70), 452 (M+H, 10), 395 (100); HPLC (method1): rt (%)=4.41 (100).

Example 94 tert-Butyl2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl-carbamate

starting from Example 60:

MS (DCI, NH₃): m/z (%)=393 (M+NH₄, 100); HPLC (method 3): rt (%)=3.97(100).

Example 955-Chloro-N-({3-[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

260 mg (0.608 mmol) of5-chloro-N-(3-{[3-fluoro4-(3-oxo4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide(from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg ofdimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5hours. 20 ml of acetonitrile are then added, and the mixture is stirredin a closed vessel in a microwave oven at 180° C. for 30 minutes. Thesolution is concentrated using a rotary evaporator and chromatographedon an RP-HPLC column. This gives 53 mg (19% of theory) of the targetcompound.

NMR (300 MHz, d₆-DMSO): δ=3.6–3.7 (m,4H), 3.85 (dd,1H), 3.95 (m,2H), 4.2(m,1H), 4.21 (s,2H), 4.85 (m,1H), 4.18 (s,2H), 7.19 (d,1H,thiophene),7.35 (dd,1H), 7.45 (t,1H), 7.55 (dd,1H), 7.67 (d,1H,thiophene), 8.95(t,1H,CONH).

Example 965-Chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

starting from Example 62:

MS (ESI): m/z (%)=359 ([M+Na]⁺, 71), 337 ([M+H]⁺, 100), Cl pattern; HPLC(method 3): rt (%)=4.39 (100). IC₅₀: 2 μM

Example 975-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

starting from Example 63:

MS (ESI): m/z (%)=458 ([M+Na]⁺, 66), 436 ([M+H]⁺, 100), Cl pattern; HPLC(method 3): rt (%)=3.89 (100). IC₅₀: 1.4 nM

Example 98N-[(3-{4-[Acetyl(cyclopropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

starting from Example 64:

MS (ESI): m/z (%)=456 ([M+Na]⁺, 55), 434 ([M+H]+, 100), Cl pattern; HPLC(method 3): rt (%)=4.05 (100). IC₅₀: 50 nM

Example 99N-[(3-{4-[Acetyl(methyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=408 (M+H, 30), 449 (M+H+MeCN, 100); HPLC (method 4):rt=3.66 min.

Example 1005-Chloro-N-({2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=404 (M+H, 45), 445 (M+H+MeCN, 100); HPLC (method 4):rt=3.77 min.

Example 101 Tert-butyl1-{4-[5-({[(5-chloro-2thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-L-prolinate

MS (ESI): m/z (%)=450 (M+H−56, 25), 506 (M+H, 100); HPLC (method 4):rt=5.13 min.

Example 1021-{4-[5-(([(5-Chloro-2-thienyl)carbonyl]aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-4-piperidinecarboxamide

MS (ESI): m/z (%)=463 (M+H, 100); HPLC (method 4): rt=2.51 min.

Example 1031-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3-piperidinecarboxamide

MS (ESI): m/z (%)=463 (M+H, 100); HPLC (method 4): rt=2.67 min.

Example 1045-Chloro-N-({2-oxo-3-[4-(4-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=434 (M+H, 40), 452 (M+H+H₂O, 100), 475 (M+H+MeCN, 60);HPLC (method 4): rt=3.44 min.

Example 1051-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-L-prolinamide

MS (ESI): m/z (%)=449 (M+H, 100); HPLC (method 4): rt=3.54 min.

Example 1065-Chloro-N-[(3-{4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=450 (M+H, 100); HPLC (method 5): rt=2.53 min.

Example 1075-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=450 (M+H, 100); HPLC (method 5): rt=2.32 min.

Example 108 Ethyl1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-piperidinecarboxylate

MS (ESI): m/z (%)=492 (M+H, 100); HPLC (method 5): rt=4.35 min.

Example 1095-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=436 (M+H, 100); HPLC (method 4): rt=2.98 min.

Example 1105-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=474 (M+H, 100); HPLC (method 4): rt=4.63 min.

Example 1115-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrrolo[3,4d]isoxazol-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=463 (M+H, 100); HPLC (method 4): rt=2.56 min.

Example 1125-Chloro-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=488 (M+H, 100); HPLC (method 4): rt=3.64 min.

Example 1135-Chloro-N-({3-[3-chloro4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=470 (M+H, 100); HPLC (method 4): rt=3.41 min.

Example 1145-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=504 (M+H, 100); HPLC (method 4): rt=3.55 min.

Example 1155-Chloro-N-({3-[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=450 (M+H, 100); HPLC (method 4): rt=3.23 min.

Example 1165-Chloro-N-({3-[3-cyano-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=461 (M+H, 100); HPLC (method 4): rt=3.27 min.

Example 1175-Chloro-N-({3-[3-chloro-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=440 (M+H, 100); HPLC (method 4): rt=3.72 min.

Example 1185-Chloro-N-({3-[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=454 (M+H, 100); HPLC (method 4): rt=3.49 min.

Example 1195-Chloro-N-({3-[3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=464 (M+H, 100); HPLC (method 4): rt=3.39 min.

Example 120N-({3-[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=465 (M+H, 100); HPLC (method 4): rt=3.07 min.

Example 1215-Chloro-N-({3-[3-methoxy-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=452 (M+H, 100); HPLC (method 4): rt=2.86 min.

Example 122N-({3-[3-Acetyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=464 (M+H, 100); HPLC (method 4): rt=3.52 min.

Example 123N-({3-[3-Amino-4-(3-oxo4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=451 (M+H, 100); HPLC (method 6): rt=3.16 min.

Example 1245-Chloro-N-({3-[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=484 (M+H, 100); HPLC (method 4): rt=3.59 min.

Example 1255-Chloro-N-({3-[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=484 (M+H, 100); HPLC (method 4): rt=3.63 min.

Example 125a5-Chloro-N-[(2-oxo-3-{4-[(3-oxo-4-morpholinyl)methyl]phenyl}-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=450 (M+H, 100); HPLC (method 4): rt=3.25 min.

Via epoxide opening with an amine and subsequent cyclization to give thecorresponding oxazolidinone, it was also possible to prepare thefollowing compounds:

Example No. Structure M.p. [° C.] IC₅₀ [μM] 126

229Z 0.013 127

159 0.0007 128

198 0.002 129

196 0.001 130

206 0.0033 130a

194 131

195 0.85 132

206 0.12 133

217 0.062 134

207 0.48 from 1-(4-amino-phenyl)-piperidin-3-ol (Tong, L. K. J. et al,;J. Amer. Chem. Soc. 1960; 82, 1988). 135

202 1.1 136

239 1.2 137

219 0.044 138

 95 0.42 139

217 1.7

Examples 14 to 16 below are working examples for the optional oxidationstep.

Example 145-Chloro-N-({(5S)-3-[3-fluoro-4-(1-oxo-1[lambda]⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

At 0° C.,5-chloro-N-({(5S)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide(0.1 g, 0.22 mmol) from Example 3 in methanol (0.77 ml) is added to asolution of sodium periodate (0.05 g, 0.23 mmol) in water (0.54 ml), andthe mixture is stirred at 0° C. for 3 h. 1 ml of DMF is then added, andthe mixture is stirred at RT for 8 h. After addition of a further 50 mgof sodium periodate, the mixture is once more stirred at RT overnight.The mixture is then admixed with 50 ml of water, and the insolubleproduct is filtered off with suction. Washing with water and dryinggives 60 mg (58% of theory) of crystals.

M.p.: 257° C.; R_(f) (silica gel, toluene/ethyl acetate 1:1)=0.54(starting material=0.46); IC₅₀ value=1.1 μM; MS (DCI) 489 (M+NH₄), Clpattern.

Example 15 Preparation of5-chloro-N-({(5S)-3-[4-(1,1-dioxo-1[lambda]⁶,4-thiazinan-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

5-Chloro-N-({(5S)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in3.32 ml of a mixture of 1 part of water and 3 parts of acetone isadmixed with 80 mg (0.66 mmol) of N-methylmorpholine N-oxide (NMO) and0.1 ml of a 2.5% strength solution of osmium tetroxide in2-methyl-2-propanol. The mixture is stirred at room temperatureovernight, and another 40 mg of NMO are added. The mixture is stirredfor a further night and then poured into 50 ml of water and extractedthree times with ethyl acetate. The organic phase gives, after dryingand concentrating, 23 mg and the aqueous phase, after removal of theinsoluble solid by filtration with suction, 19 mg (in total 39% oftheory) of the target compound.

M.p.: 238° C.; R_(f) (toluene/ethyl acetate 1:1)=0.14 (startingmaterial=0.46); IC₅₀ value=210 nM; MS (DCI): 505 (M+NH₄), Cl pattern.

Example 165-Chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamideN-oxide

is obtained by treating5-chloro-N-{[(5S)-3-(3-fluoro4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamidefrom Example 1 with the magnesium salt of monoperoxyphthalic acid. MS(ESI): 456 (M+H, 21%, Cl pattern), 439 (100%).

The Examples 31 to 35 and 140 to 147 below refer to the optionalamidination step.

General Method for Preparing Amidines and Amidine Derivatives Startingfrom Cyanomethylphenyl-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamideDerivatives

The cyanomethylphenyl-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamidederivative in question (1.0 eq.) is, together with triethylamine (8.0eq.), stirred at RT in a saturated solution of hydrogen sulphide inpyridine (about 0.05–0.1 mol/l) for one to two days. The reactionmixture is diluted with ethyl acetate (EtOAc) and washed with 2 Nhydrochloric acid. The organic phase is dried with MgSO₄, filtered andconcentrated under reduced pressure.

The crude product is dissolved in acetone (0.01–0.1 mol/l) and admixedwith methyl iodide (40 eq.). The reaction mixture is stirred at roomtemperature (RT) for 2 to 5 h and then concentrated under reducedpressure.

The residue is dissolved in methanol (0.01–0.1 mol/l) and, to preparethe unsubstituted amidines, admixed with ammonium acetate (3 eq.) andammonium chloride (2 eq.). To prepare the substituted amidinederivatives, primary or secondary amines (1.5 eq.) and acetic acid (2eq.) are added to the methanolic solution. After 5–30 h, the solvent isremoved under reduced pressure and the residue is purified bychromatography over an RP8 silica gel column (water/acetonitrile9/1–1/1+0.1% trifluoroacetic acid).

The following compounds were prepared in an analogous manner:

Example 31N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=393 (M+H, 100); HPLC (method 4): rt=2.63 min

Example 325-Chloro-N-({3-[3-(4,5dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=419 (M+H, 100); HPLC (method 4): rt=2.61 min

Example 335-Chloro-N-[(3-{3-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=463 (M+H, 100); HPLC (method 4): rt=2.70 min

Example 345-Chloro-N-[(3-{3-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=447 (M+H, 100); HPLC (method 4): rt=2.82 min

Example 35N-({3-[3-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=393 (M+H, 100); HPLC (method 4): rt=2.60 min

Example 1405-Chloro-N-({3-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=419 (M+H, 100); HPLC (method 4): rt=2.65 min

Example 1415-Chloro-N-[(3-{4-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=463 (M+H, 100); HPLC (method 4): rt=2.65 min

Example 1425-Chloro-N-[(3-{4-[2-imino-2-(1-piperidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=461 (M+H, 100); HPLC (method 4): rt=2.83 min

Example 1435-Chloro-N-[(3-{4-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=447 (M+H, 100); HPLC (method 4): rt=2.76 min

Example 1445-Chloro-N-[(3-{4-[2-(cyclopentylamino)-2-iminoethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=461 (M+H, 100); HPLC (method 4): rt=2.89 min

Example 1455-Chloro-N-{[3-(4-{2-imino-2-[(2,2,2-trifluoroethyl)amino]ethyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

MS (ESI): m/z (%)=475 (M+H, 100); HPLC (method 4): rt=2.79 min

Example 146N-({3-[4-(2-Anilino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

MS (ESI): m/z (%)=469 (M+H, 100); HPLC (method 4): rt=2.83 min

Example 1475-Chloro-N-[(3-{4-[2-imino-2-(2-pyridinylamino)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=470 (M+H, 100); HPLC (method 4): rt=2.84 min

Examples 148 to 151 below refer to the removal of BOC amino protectivegroups:

General Method for Removing Boc Protective Groups(tert-butyloxycarbonyl)

Aqueous trifluoroacetic acid (TFA, about 90%) is added dropwise to anice-cooled solution of a tert-butyloxycarbonyl-(Boc) protected compoundin chloroform or dichloromethane (about 0.1 to 0.3 mol/l). After about15 min, ice-cooling is removed and the mixture is stirred at roomtemperature for approximately 2–3 h, and the solution is thenconcentrated and dried under high vacuum. The residue is taken up indichloromethane or dichloromethane/methanol and washed with saturatedsodium bicarbonate or 1N sodium hydroxide solution. The organic phase iswashed with saturated sodium chloride solution, dried over a littlemagnesium sulphate and concentrated. If appropriate, purification iscarried out by crystallization from ether or ether/dichloromethanemixtures.

The following compounds were prepared in an analogous manner from thecorresponding Boc-protected precursors:

Example 148N-({3-[4-(Aminomethyl)phenyl]-2-oxo1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide

starting from Example 92:

MS (ESI): m/z (%)=349 (M−NH₂, 25), 305 (100); HPLC (method 1): rt(%)=3.68 (98). IC₅₀: 2.2 μM

Example 149N-{[3-(4-Aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide

starting from Example 93:

MS (ESI): m/z (%)=352 (M+H, 25); HPLC (method 1): rt (%)=3.50 (100).IC₅₀: 2 μM

An alternative enantiomerically pure synthesis of this compound is shownin the scheme below (cf. also Delalande S. A., DE 2836305,1979; Chem.Abstr. 90, 186926):

Example 1505-Chloro-N-({3-[4-(glycylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

starting from Example 152:

MS (ES-pos): m/z (%)=408 (100); HPLC (method 3): rt (%)=3.56 (97). IC₅₀:2 μM

Example 1515-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl-1,3-oxazolidin-2-one

starting from Example 60:

MS (ESI): m/z (%)=276 (M+H, 100); HPLC (method 3): rt (%)=2.99 (100).IC₅₀: 2 μM

The Examples 152 to 166 below refer to the amino group derivatization ofaniline- or benzylamine-substituted oxazolidinones using variousreagents:

Example 1525-Chloro-N-({3-[4-(N-tert-butyloxycarbonyl-glycylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

At 0° C., 754 mg (2.1 mmol) ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5chloro-2-thiophenecarboxamide(from Example 149) are added to a solution of 751 mg (4.3 mmol) ofBoc-glycine, 870 mg (6.4 mmol) of HOBT (1-hydroxy-1H-benzotriazole×H₂O),1790 mg (4.7 mmol) of HBTU[O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate]and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DM/CH₂Cl₂(1:1). The mixture is stirred at room temperature overnight and thendiluted with water. The precipitated solid is filtered off and dried.Yield: 894 mg (79.7% of theory);

MS (DCI, NH₃): m/z (%)=526 (M+NH₄, 100); HPLC (method 3): rt (%)=4.17(97).

Example 153N-[(3-{4-[(Acetylamino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

At 0° C., a mixture of 30 mg (0.082 mmol) ofN-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide(from Example 148) in 1.5 ml of absolute THF and 1.0 ml of absolutedichloromethane, and 0.02 ml of absolute pyridine is mixed with aceticanhydride (0.015 ml, 0.164 mmol). The mixture is stirred at roomtemperature overnight. Addition of ether and crystallization affords theproduct. Yield: 30 mg (87% of theory),

MS (ESI): m/z (%)=408 (M+H, 18), 305 (85); HPLC (method 1): rt (%)=3.78(97). IC₅₀: 0.6 μM

Example 154N-{[3-(4-{[(Aminocarbonyl)amino]methyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophenecarboxamide

At room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate areadded dropwise to a mixture of 30 mg (0.082 mmol) ofN-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 mlof dichloromethane. The mixture is stirred overnight and, after additionof ether, the product is then obtained by filtration. Yield: 21.1 mg(52% of theory),

MS (ESI): m/z (%)=409 (M+H, 5), 305 (72); HPLC (method 1): rt (%)=3.67(83). IC₅₀: 1.3 μM

General Method for AcylatingN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamidewith Carbonyl Chlorides:

Under argon, an approximately 0.1 molar solution ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide(from Example 149) (1.0 eq.) in absolute dichloromethane/pyridine (19:1)is added dropwise to the appropriate acid chloride (2.5 eq.). Themixture is stirred overnight and then admixed with about 5 eq. of PStrisamine (Argonaut Technologies) and 2 ml of absolute dichloromethane.The mixture is stirred gently for 1 h and then filtered off, and thefiltrate is concentrated. If appropriate, the products are purified bypreparative RP-HPLC.

The following compounds were prepared in an analogous manner:

Example 155N-({3-[4-(Acetylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide

LC-MS: m/z (%)=394 (M+H, 100); LC-MS (method 6): rt (%)=3.25 (100) IC₅₀:1.2 μM

Example 1565-Chloro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)amino]phenyl}-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

LC-MS: m/z (%)=462 (M+H, 100); LC-MS (method 6): rt (%)=3.87 (100).IC₅₀: 1.3 μM

Example 1575-Chloro-N-[(3-{4-[(methoxyacetyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)-methyl]-2-thiophenecarboxamide

LC-MS: m/z (%)=424 (M+H, 100); LC-MS (method 6): rt (%)=3.39 (100).IC₅₀: 0.73 μM

Example 158N-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3,5-dimethyl-4-isoxazolecarboxamide

LC-MS: m/z (%)=475 (M+H, 100). IC₅₀: 0.46 μM

Example 1595-Chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

An ice-cooled solution of 26.4 mg (0.15 mmol) of3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) oftriethylamine in 3.5 ml of absolute dichloromethane is admixed with 35mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149). After 30 min,ice-cooling is removed and the mixture is stirred at room temperatureovernight, and 150 mg (about 5.5 eq.) of PS-trisamine (ArgonautTechnologies) and 0.5 ml of dichloromethane are then added. Thesuspension is stirred gently for 2 h and filtered (the resin is washedwith dichloromethane/methanol), and the filtrate is concentrated. Theproduct is purified by preparative RP-HPLC. Yield: 19.6 mg (40% oftheory),

LC-MS: m/z (%)=492 (M+H, 100); LC-MS (method 5): rt (%)=3.82 (91). IC₅₀:1.7 μM

Example 1605-Chloro-N-({3-[4-(1,1-dioxido-2-isothiazolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

A mixture of 13.5 mg (0.027 mmol) of5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (fromExample 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml ofDMF is heated at 100° C. for 2 h. After cooling, the mixture is dilutedwith dichloromethane and washed with water. The organic phase is driedand concentrated. The residue is purified by preparative thin-layerchromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8mg (14.4% of theory),

MS (ESI): m/z (%)=456 (M+H, 15), 412 (100); LC-MS (method 4): rt(%)=3.81 (90). IC₅₀: 0.14 μM

Example 1615-Chloro-N-[((5S)-3-{4(5-chloropentanoyl)amino]phenyl]-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

0.5 g (1.29 mmol) ofN-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide(from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixedwith 0.2 g (1.29 mmol) of 5-chlorovaleryl chloride and 0.395 ml (2.83mmol) of triethylamine. The mixture is concentrated under reducedpressure and chromatographed over silica gel using a toluene/ethylacetate=1:1->ethyl acetate gradient. This gives 315 mg (52% of theory)of a solid.

M.p.: 211° C.

Example 1625-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

Under inert conditions, 5 ml of DMSO are admixed with 30 mg of NaH (60%in paraffin oil), and the mixture is heated at 75° C. for 30 min, untilthe evolution of gas has ceased. A solution of 290 mg (0.617 mmol) of5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophene-carboxamide(from Example 161) in 5 ml of methylene chloride is then added dropwise,and the mixture is stirred at room temperature overnight. The reactionis terminated and the mixture is poured into 100 ml of water andextracted with ethyl acetate. The evaporated organic phase ischromatographed on an RP-8 column and the product is eluted withacetonitrile/water. This gives 20 mg (7.5% of theory) of the targetcompound.

M.p.: 205° C.; NMR (300 MHz, d₆-DMSO): δ=1.85 (m,4H), 2.35 (m,2H), 3.58(m,4H), 3.85 (m,1H), 4.2 (t,1H), 4.82 (m,1H), 7.18 (d,1H,thiophene),7.26 (d,2H), 7.5 (d,2H), 2.68 (d,1H,thiophene), 9.0 (t,1H,CONH). IC₅₀:2.8 nM

Example 1635-Chloro-N-[((5S)-3-{4-[(3-bromopropionyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

is obtained in an analogous manner from Example 149.

Example 1645-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-azetidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

is obtained in an analogous manner by cyclization of the open-chainbromopropionyl compound from Example 163 using NaH/DMSO.

MS (ESI): m/z (%)=406 ([M+H]⁺, 100), Cl pattern. IC₅₀: 380 nM

Example 165 tert-Butyl4-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3oxazolidin-3-yl]phenyl}-3,5-dioxo-1-piperazinecarboxylate

A solution of 199 mg (0.85 mmol) of Boc-iminodiacetic acid, 300 mg (2.2mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7mmol) of HBTU is admixed with 300 mg (0.85 mmol) ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide in 6 ml of a mixture of DMF anddichloromethane (1:1). The mixture is stirred overnight, diluted withdichloromethane and then washed with water, saturated ammonium chloridesolution, saturated sodium bicarbonate solution, water and saturatedsodium chloride solution. The organic phase is dried over magnesiumsulphate and concentrated. The crude product is purified by silica gelchromatography (dichloromethane/methanol 98:2). Yield: 134 mg (29% oftheory);

MS (ESI): m/z (%)=571 (M+Na, 82), 493 (100); HPLC (method 3): rt(%)=4.39 (90). IC₅₀: 2 μM

Example 166 N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1 pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamidetrifluoroacetate

N2-(tert-Butoxycarbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionineamide

429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) ofN-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide, and 527 mg (3.44 mmol) of HOBThydrate are dissolved in 35 ml of DMF and admixed with 660 mg (3.441mmol) of EDCI hydrochloride and then dropwise with 689 mg (5.334 mmol)of N-ethyl-diisopropylamine. The mixture is stirred at room temperaturefor two days. The resulting suspension is filtered off with suction andthe residue is washed with DMF. The combined filtrates are admixed witha little silica gel, concentrated under reduced pressure andchromatographed over silica gel using a toluene->T10EA7 gradient. Thisgives 170 mg (17% of theory) of the target compound of melting point183° C.

R_(f) (SiO₂, toluene/ethyl acetate=1:1):0.2. ¹H-NMR (300 MHz, d₆-DMSO):δ=1.4 (s,1H,BOC), 1.88–1.95 (m,2H), 2.08 (s,3H,SMe), 2.4–2.5 (m,2H,partially obscurbed by DMSO), 3.6 (m,2H), 3.8 (m,1H), 4.15 (m,2H), 4.8(m,1H), 7.2 (1H, thiophene), 7.42 (d, part of an AB system, 2H), 7.6 (d,part of an AB system, 2H), 7.7 (d, 1H, thiophene), 8.95 (t,1H, CH₂NHCO),9.93 (bs, 1H,NH).

tert-Butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate

170 mg (0.292 mmol) ofN2-(tert-butoxycarbonyl)-N1-(4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionine-amideare dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) oftrimethylsulphonium iodide and 60.4 mg (0.437 mmol) of potassiumcarbonate, and the mixture is stirred at 80° C. for 3.5 hours. Themixture is then concentrated under high vacuum and the residue is washedwith ethanol. 99 mg of the target compound remain.

¹H-NMR (300 MHz, d₆-DMSO): δ=1.4 (s,1H,BOC), 1.88–2.05 (m,1; H), 2.3–2.4(m,1H), 3.7–3.8 (m,3H), 3.8–3.9 (m,1H), 4.14.25 (m,1H), 4.25–4.45(m,1H), 4.75–4.95 (m,1H), 7.15 (1H, thiophene), 7.25 (d,1H), 7.52 (d,part of an AB system, 2H), 7.65 (d, part of an AB system, 2H), 7.65 (d,1H, thiophene), 9.0 (broad s,1H).

N[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamidetrifluoroacetate

97 mg (0.181 mmol) of tert-butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylenechloride, 1.5 ml of trifluoroacetic acid are added and the mixture isstirred at room temperature for 1 hour. The mixture is then concentratedunder reduced pressure and the residue is purified on an RP-HPLC(acetonitrile/water/0.1% TFA gradient). Evaporation of the appropriatefraction gives 29 mg (37% of theory) of the target compound of meltingpoint 241° C. (decomp.).

R_(f) (SiO₂,EtOH/TEA=17:1) 0.19. ¹H-NMR (300 MHz, d₆-DMSO): δ=1.92–2.2(m,1H), 2.4–2.55 (m,1H, partially obscured by DMSO peak), 3.55–3.65(m,2H), 3.75–3.95 (m,3H), 4.1–4.3 (m,2H), 4.75–4.9 (m,1H), 7.2 (1H,thiophene), 7.58 (d, part of an AB system, 2H), 7.7 (d, part of an ABsystem, 2H), 7.68 (d, 1H, thiophene), 8.4 (broad s,3H, NH3), 8.9(t,1H,NHCO).

The Examples 167 to 170 below refer to the introduction of sulphonamidegroups in phenyl-substituted oxazolidinones:

General Method for Preparing Substituted Sulphonamides Starting from5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

Under argon and at 5° C.,5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide(from Example 96) is added to chlorosulphonic acid (12 eq.). Thereaction mixture is stirred at room temperature for 2 h and then pouredinto ice-water. The resulting precipitate is filtered off, washed withwater and dried.

Under argon and at room temperature, the precipitate is then dissolvedin tetrahydrofuran (0.1 mol/l) and admixed with the appropriate amine (3eq.), triethylamine (1.1 eq.) and dimethylaminopyridine (0.1 eq.). Thereaction mixture is stirred for 1–2 h and then concentrated underreduced pressure. The desired product is purified by flashchromatography (dichloromethane/methanol mixtures).

The following compounds were prepared in an analogous manner:

Example 1675-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinylsulphonyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=492 ([M+Na]⁺, 100), 470 ([M+H]⁺, 68), Cl pattern; HPLC(method 3): rt (%)=4.34 (100). IC₅₀: 0.5 μM

Example 1685-Chloro-N-[(3-{4-[(4-methyl-1-piperazinyl)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=499 ([M+H]⁺, 100), Cl pattern; HPLC (method 2): rt(%)=3.3 (100).

Example 1695-Chloro-N-({2-oxo-3-[4-(1-piperidinylsulphonyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

MS (ESI): m/z (%)=484 ([M+H]⁺, 100), Cl pattern; HPLC (method 2): rt(%)=4.4 (100).

Example 1705-Chloro-N-[(3-{4-[(4-hydroxy-1-piperidinyl)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

MS (ESI): m/z (%)=500 ([M+H]⁺, 100), Cl pattern; HPLC (method 3): rt(%)=3.9 (100).

Example 1715-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

780 mg (1.54 mmol) of tert-butyl1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinateare dissolved in 6 ml of dichloromethane and 9 ml of trifluoroaceticacid, and the mixture is stirred at 40° C. for two days. The reactionmixture is then concentrated and stirred with ether and 2N aqueoussodium hydroxide solution. The aqueous phase is concentrated and stirredwith ether and 2N hydrochloric acid. The organic phase of thisextraction is dried over MgSO₄, filtered and concentrated. The crudeproduct is chromatographed over silica gel (CH₂Cl₂/EtOH/conc. aqu. NH₃sol.=100/1/0.1 to 20/1/0.1). This gives 280 mg (40% of theory) of theproduct.

MS (ESI): m/z (%)=406 (M+H, 100); HPLC (method 4): rt=3.81 min.

HPLC Parameter and LC-MS Parameter for the HPLC and LC-MS Data Given inthe Examples Above (the Unit of the Retention Time (rt) is Minutes):

-   [1] Column: Kromasil C18, L-R temperature: 30° C., flow rate=0.75 ml    min⁻¹, eluent: A=0.01 M HClO₄, B=CH₃CN, gradient:->0.5 min 98%    A->4.5 min 10% A->6.5 min 10% A-   [2] Column: Kromasil C18 60*2, L-R temperature: 30° C., flow    rate=0.75 ml min⁻¹, eluent: A=0.01 M H₃PO₄, B=CH₃CN, gradient:->0.5    min 90% A->4.5 min 10% A->6.5 min 10% A-   [3] Column: Kromasil C18 60*2, L-R temperature: 30° C., flow    rate=0.75 ml min⁻¹, eluent: A=0.005 M HClO₄, B=CH₃CN, gradient:    ->0.5 min 98% A->4.5 min 10% A ->6.5 min 10% A-   [4] Column: Symmetry C18 2.1×50 mm, column oven: 50° C., flow    rate=0.6 ml min⁻¹, eluent: A=0.6 g 30% strength HCl/l of water,    B=CH₃CN, gradient: 0.0 min 90% A ->4.0 min 10% A ->9 min 10% A-   [5] MHZ-2Q, Instrument Micromass Quattro LCZ Column Symmetry C18, 50    mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate 0.5 ml min⁻¹ ,    eluent A=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid,    gradient: 0.0 min 10% A->4 min 90% A->6 min 90% A-   [6] MHZ-2P, Instrument Micromass Platform LCZ Column Symmetry C18,    50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹,    eluent A=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid,    gradient: 0.0 min 10% A->4 min 90% A->6 min 90% A-   [7] MHZ-7Q, Instrument Micromass Quattro LCZ Column Symmetry C18, 50    mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹,    eluent A=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid,    gradient: 0.0 min 5% A->1 min 5% A->5 min 90% A->6 min 90% A    General Method for Preparing Oxazolidinones of the General Formula B    by Solid-phase-supported Synthesis

Reactions with different resin-bonded products were carried out in a setof separated reaction vessels.

5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A(prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanateusing LiBr/Bu₃PO in xylene analogously to U.S. Pat. No. 4,128,654, Ex.2)(1.20 g, 3.75 mmol) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmol)were dissolved in DMSO (70 ml), admixed with a secondary amine (1.1 eq.,amine component 1) and reacted at 55° C. for 5 h. TentaGel SAM resin(5.00 g, 0.25 mmol/g) was added to this solution, and the mixture wasreacted at 75° C. for 48 h. The resin was filtered, washed repeatedlywith methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane(DCM) and diethyl ether and dried. The resin (5.00 g) was suspended indichloromethane (80 ml), admixed with DEEA (10 eq.) and5-chlorothiophene-2-carbonyl chloride [prepared by reacting5-chlorothiophene-2-carboxylic acid (5 eq.) and1-chloro-1-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at roomtemperature for 15 minutes] and the mixture was reacted at roomtemperature for 5 h. The resulting resin was filtered, washed repeatedlywith MeOH, DCM and diethyl ether and dried. The resin was then suspendedin DMF/water (v/v 9:2, 80 ml), admixed with SnCl₂*2H₂O (5 eq.) andreacted at room temperature for 18 h. The resin was washed repeatedlywith MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resinwas suspended in DCM, admixed with DIEA (10 eq.) and, at 0° C., with anacid chloride (5 eq. of acid derivative 1), and the mixture was reactedat room temperature overnight. Prior to the reaction, carboxylic acidswere converted into the corresponding acid chlorides by reaction with1-dimethylamino-1-chloro-2-methylpropene (1 eq., based on the carboxylicacid) in DCM at room temperature for 15 min. The resin was washedrepeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether and dried.If the acid derivative 1 used was an Fmoc-protected amino acid, the Fmocprotective group was removed in the last reaction step by reaction withpiperidine/DMF (v/v, 1/4) at room temperature for 15 minutes, and theresin was washed with DMF, MeOH, DCM and diethyl ether and dried. Theproducts were then removed from the solid phase using trifluoroaceticacid (TFA)/DCM (v/v, 1/1), the resin was filtered off and the reactionsolutions were concentrated. The crude products were filtered oversilica gel (DCM/MeOH, 9:1) and evaporated, giving a set of products B.

Compounds which were prepared by solid-phase-supported synthesis:

Example 172N-({3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

Analogously to the general procedure for preparing the derivatives B, 5g (1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine asamine derivative 1. The aniline obtained after reduction with SnCl₂*2H₂Owas, without any further acylation step, removed from the solid phaseand concentrated. The crude product was partitioned between ethylacetate and NaHCO₃ solution and the organic phase was salted out usingNaCl, decanted and evaporated to dryness. This crude product waspurified by vacuum flash chromatography over silica gel(dichloromethane/ethyl acetate, 3:1–1:2).

¹H-NMR (300 MHz, CDCl₃): 1.95–2.08, br, 4 H; 3.15–3.30, br, 4 H;3.65–3.81, m, 2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, 1 H; 6.46,dd, 1 H; 6.72, dd, 1 H; 6.90, dd, 1 H; 6.99, dd, 1 H; 7.03, dd, 1 H;7.29, d, 1 H.

Example 173N-[(3-{3-(B-Alanylamino)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

Analogously to the general procedure for preparing the derivatives B, 5g (1.25 mmol) of TentaGel SAM resin were reacted with azetidine as aminederivative 1 and Fmoc-β-alanine as acid derivative 1. The crude productobtained after the removal was stirred in methanol at room temperaturefor 48 h and evaporated to dryness. This crude product was purified byreversed phase HPLC using a water/TFA/acetonitrile gradient.

¹H-NMR (400 MHz, CD₃OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H;3.62, t, 2 H; 3.72, dd, 1 H; 3.79, dd, 1 H; 4.01, dd, 1 H; 4.29, dd, 2H; 4.43, t, 2 H; 4.85–4.95, m, 1 H; 7.01, d, 1 H; 4.48–7.55, m, 2 H;7.61, d, 1 H; 7.84, d, 1 H.

Example 174N-({3-[4-(3-Amino-1-pyrrolidinyl)-3-nitrophenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

Analogously to the general procedure for preparing the derivatives B,130 mg (32.5 μmol) of TentaGel SAM resin were reacted with tert-butyl3-pyrrolidinylcarbamate as amine derivative 1. The nitrobenzenederivative obtained after the acylation with 5-chlorothiophenecarboxylicacid was removed from the solid phase and concentrated. This crudeproduct was purified by reversed phase HPLC using awater/TFA/acetonitrile gradient.

¹H-NMR (400 MHz, CD₃OH): 2.07–2.17, m, 1 H; 2.39–2.49, m, 1 H;3.21–3.40, m, 2 H; 3.45, dd, 1 H; 3.50–3.60, m, 1 H; 3.67, dd, 1 H;3.76, dd, 1 H; 3.88–4.00, m, 2 H; 4.14–4.21, t, 1 H; 4.85–4.95, m, 1 H;7.01, d, 1 H; 7.11, d, 1 H; 7.52, d, 1 H; 7.66, dd, 1 H; 7.93, d, 1 H.

Example 175N-({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

Analogously to the general procedure for preparing the derivatives B,130 mg (32.5 μmol) of TentaGel SAM resin were reacted with piperidine asamine derivative 1. The aniline obtained after the reduction was,without any further acylation step, removed from the solid phase andconcentrated. This crude product was purified by reversed phase HPLCusing a water/TFA/acetonitrile gradient.

¹H-NMR (400 MHz, CD₃OH): 1.65–1.75, m, 2 H; 1.84–1.95, m, 4 H;3.20–3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd,1 H; 4.804.90, m, 1 H; 7.00, d, 1 H; 7.05, dd, 1 H; 7.30–7.38, m, 2H;7.50, d, 1 H.

Example 176N-({3-[3-(Acetylamino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

Analogously to the general procedure for preparing the derivatives B,130 mg (32.5 μmol) of TentaGel SAM resin were reacted pyrrolidine asamine derivative 1 and acetyl chloride as acid derivative 1. The crudeproduct was partitioned between ethyl acetate NaHCO₃ solution and theorganic phase was salted out using NaCl, decanted and evaporated todryness. This crude product was purified by vacuum flash chromatographyover silica gel (dichloromethane/ethyl acetate, 1:1–0:1).

¹H-NMR (400 MHz, CD₃OH): 1.93–2.03, br, 4 H; 2.16, s, 3 H; 3.20–3.30,br, 4 H; 3.70, d, 2 H; 3.86, dd, 1H; 4.10, dd, 1 H; 4.14, dd, 1 H;4.80–4.90, m, 1 H; 7.00, d, 1 H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1H; 7.60, d, 1 H.

The following compounds were prepared analogously to the generalprocedure.

Ret. HPLC Example Structure time [%] 177

2.62 79.7 178

2.49 33.7 179

4.63 46.7 180

3.37 44.8 181

2.16 83 182

2.31 93.3 183

2.7 100 184

3.91 51 185

2.72 75.2 186

3.17 46 187

4.61 50.2 188

3.89 56.6 189

3.37 52.9 190

3.6 63.9 191

2.52 70.1 192

3.52 46.6 193

2.87 50.1 194

3.25 71.1 195

2.66 67 196

2.4 52.1 197

3.13 48.9 198

2.67 75.5 199

2.72 65.7 200

2.71 57.3 201

2.22 100 202

3.89 75.7 203

3.19 49.6 204

2.55 88.2 205

2.44 68.6 206

2.86 71.8 207

2.8 63.6 208

2.41 77 209

2.56 67.9 210

3.67 78.4 211

2.54 69.8 212

3.84 59.2 213

2.41 67.8 214

2.41 75.4 215

4.01 81.3 216

3.46 49.5 217

4.4 60.2 218

3.79 70.9 219

4.57 51.5 220

2.68 100 221

4.53 63.5 222

2.66 89.2 223

4.76 69.3 224

3.45 77.4 225

3.97 63.2 226

3.94 61.4 227

4.15 66.3 228

4.41 55.1 229

2.83 41.1 230

2.7 83 231

4.39 64.2 232

4.85 74.9 233

4.17 41 234

4.21 61.8 235

2.75 100 236

3.94 50 237

4.65 75.8 238

4.4 75.3 239

4.24 62.2 240

4.76 75.1 241

4.17 72.5 242

4.6 74.8 243

4.12 51.6 244

4.71 66.2 245

4.86 62 246

5.23 58.3 247

4.17 72.4 248

3.35 59.6 249

2.41 60.3 250

3.31 65.2 251

2.86 36.5 252

2.69 89.8 253

2.81 67.4 254

2.19 75.4

All products of the solid-phase-supported synthesis were characterizedby LC-MS. As standard, the following separation system was used: HP 1100with UV detector (208–400 nm), oven temperature 40° C., Waters-SymmetryC18 column (50 mm×2.1 mm, 3.5 μm), mobile phase A: 99.9%acetonitrile/0.1% formic acid, mobile phase B: 99.9% water/0.1% formicacid; gradient:

Time A: % B: % flow rate 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50 6.0090.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50

The substances were detected using a Micromass Quattro LCZ MS,ionization: ESI positive/negative.

In the structures listed above which comprise the radical(s)

—O, what is meant is in each case a

or —OH function.

1. A compound of the formula (I)

characterized in that R¹ represents an optionally benzo-fused thiophenegroup which may optionally be mono- or polysubstituted by a radicalselected from the group consisting of halogen; cyano; nitro; amino;aminomethyl; (C₁–C₈)-alkyl which for its part may optionally be mono- orpolysubstituted by halogen; (C₃–C₇)-cycloalkyl; (C₁–C₈)-alkoxy;imidazolinyl; —C(═NH)NH₂; carbamoyl; and mono- anddi-(C₁–C₄)-alkyl-aminocarbonyl, R² represents D-M-A-, where

the radical “A” represents optionally substituted the radical “D”represents

 and the radical “M” represents a covalent bond; where the group “A”defined above may optionally be mono- or polysubstituted by a radicalselected from the group consisting of halogen; trifluoromethyl; cyano;nitro; carbamoyl; (C₁–C₆)-alkanoyl; —OR³⁰; —NR³⁰R³¹, and (C₁–C₆)-alkyl,where R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁–C₄)-alkyl, or C(O)R³³, where R³³represents (C₁–C₄)-aminoalkyl, or (C₁–C₈)-alkyl, R³, R⁴, R⁵, R⁶, R⁷ andR⁸ are identical or different and each represents hydrogen or represents(C₁–C₆)-alkyl or a pharmaceutically acceptable salt or hydrate thereofexcept for compounds of the formula (I) in which the radical R¹ is anunsubstituted 2-thiophene radical and the radical R² is simultaneously amono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are each simultaneously hydrogen.
 2. The compound of theformula (I) according to claim 1, characterized in that R¹ representsthiophene which may optionally be mono- or polysubstituted by halogen,amino, aminomethyl or (C₁–C₈)-alkyl, where the (C₁–C₈)-alkyl radical forits part may optionally be mono- or polysubstituted by halogen, R²represents D-M-A-, where the radical “A” represents optionallysubstituted

the radical “D” represents

 and the radical “M” represents a covalent bond; where the group “A”defined above may optionally be mono- or polysubstituted by a radicalselected from the group consisting of halogen; trifluoromethyl; cyano;nitro; carbamoyl; (C₁–C₆)-alkanoyl; —OR³⁰; —NR³⁰R³¹, and (C₁–C₆)-alkyl,where R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁–C₄)-alkyl, (C₁–C₄)-alkanoyl, or(C₁–C₄)-alkylaminocarbonyl, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical ordifferent and each represents hydrogen or represents (C₁–C₆)-alkyl or apharmaceutically acceptable salt or hydrate thereof except for compoundsof the formula (I) in which the radical R¹ is an unsubstituted2-thiophene radical and the radical R² is simultaneously a mono- orpolysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ andR⁸ are each simultaneously hydrogen.
 3. The compound of the formula (I)according to claim 1, characterized in that R¹ represents thiophenewhich may optionally be mono- or polysubstituted by halogen or by(C₁–C₈)-alkyl, where the (C₁–C₈)-alkyl radical for its part mayoptionally be mono- or polysubstituted by halogen, R² represents D-M-A-,where: the radical “A” represents optionally substituted

the radical “D” represents

 and the radical “M” represents a covalent bond; where the group “A”defined above may optionally be mono- or polysubstituted by a radicalselected from the group consisting of halogen; trifluoromethyl; cyano;(C₁–C₃)-alkanoyl; —OH; —NR³⁰R³¹; and (C₁–C₄)-alkyl; where R³⁰ and R³¹are identical or different and independently of one another eachrepresents hydrogen, (C₁–C₄)-alkyl or (C₁–C₃)-alkanoyl, R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are identical or different and each represents hydrogen orrepresents (C₁–C₆)-alkyl or a pharmaceutically acceptable salt orhydrate thereof except for compounds of the formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen. 4.The compound of the formula (I) according to claim 1, characterized inthat R¹ represents 2-thiophene which may optionally be substituted inthe 5-position by a radical selected from the group consisting ofchlorine, bromine, methyl and trifluoromethyl, R² represents D-M-A-,where: the radical “A” represents optionally substituted

the radical “D” represents

 and the radical “M” represents a covalent bond; where the group “A”defined above may optionally be mono- or polysubstituted by a radicalselected from the group consisting of halogen; trifluoromethyl; cyano;(C₁–C₃)-alkanoyl; —OH; —NR³⁰R³¹; and (C₁–C₄)-alkyl; where R³⁰ and R³¹are identical or different and independently of one another eachrepresents hydrogen, (C₁–C₄)-alkyl or (C₁–C₃)-alkanoyl, R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are identical or different and each represents hydrogen orrepresents (C₁–C₄)-alkyl or a pharmaceutically acceptable salt orhydrate thereof except for compounds of the formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen. 5.The compound of the formula (I) according to claim 1, characterized inthat R¹ represents 2-thiophene which is substituted in the 5-position bya radical selected from the group consisting of chlorine, bromine,methyl and trifluoromethyl, R² represents D-A-, where: the radical “A”represents

the radical “D” represents

 where the group “A” defined above may optionally be mono- ordisubstituted in the meta position with respect to the point ofattachment to the oxazolidinone, by a radical selected from the groupconsisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyland cyano, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ each represent hydrogen or apharmaceutically acceptable salt or hydrate thereof.
 6. The compoundhaving the following formula

or a pharmaceutically acceptable salt or hydrate thereof.
 7. Process forpreparing the substituted oxazolidinone of claim 1, where eitheraccording to a process alternative (A) a compound of the formula (II)

 in which the radicals R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedin claim 1 is reacted with carboxylic acid of the formula (III)

 in which the radical R¹ is as defined in claim 1, or else with acorresponding carbonyl halide, or else with a corresponding symmetric ormixed carboxylic anhydride of the carboxylic acid of the formula (III)defined above in an inert solvent, if appropriate in the presence of anactivating or coupling agent and/or a base, to give a compound of theformula (I)

 in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, or else according to a process alternative (B) acompound of the formula (IV)

 in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedin claim 1, is converted, using a suitable selective oxidizing agent inan inert solvent, into the corresponding epoxide of the formula (V)

 in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedin claim 1, and, by reaction in an inert solvent, if appropriate in thepresence of a catalyst, with an amine of the formula (VI)R²—NH₂  (VI),  in which the radical R² is as defined in claim 1, acompound of the formula (VII)

 in which the radicals it R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, is initially prepared and, subsequently, in an inertsolvent in the presence of phosgene or a phosgene equivalent, cyclizedto give a compound of the formula (I)

 in which the radicals it R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, where—both for process alternative (A) and forprocess alternative (B)—in the case where R² contains a 3- to 7-memberedsaturated or partially unsaturated cyclic hydrocarbon radical having oneor more identical or different heteroatoms from the group consisting ofN and S, an oxidation with a selective oxidizing agent to afford thecorresponding sulphone, sulphoxide or N-oxide may follow and/orwhere—both for process alternative (A) and for process alternative(B)—in the case where the compound prepared in this manner has a cyanogroup in the molecule, an amidination of this cyano group by customarymethods may follow and/or where—both for process alternative (A) and forprocess alternative (B)—in the case where the compound prepared in thismanner has a BOC amino protective group in the molecule, removal of thisBOC amino protective group by customary methods may follow and/orwhere—both for process alternative (A) and for process alternative(B)—in the case where the compound prepared in this manner has ananiline or benzylamine radical in the molecule, a reaction of this aminogroup with a carboxylic acid, carboxylic anhydride, carbonyl chloride,isocyanate, sulphonyl chloride or alkyl halide to give the correspondingderivative may follow and/or where—both for process alternative (A) andfor process alternative (B)—in the case where the compound prepared inthis manner has a phenyl ring in the molecule, a reaction withchlorosulphonic acid and subsequent reaction with an amine to give thecorresponding sulphonamide may follow.
 8. A pharmaceutical compositioncomprising at least one compound of the formula (I) according to claim 1and one or more pharmacologically acceptable auxiliaries or excipients.9. A method for treatment of atherosclerosis comprising administering aneffective amount of a compound of claim 1 to a patient in need thereof.10. The compound of claim 2 or 3 wherein R¹ represents an optionallysubstituted 2-thiophene group, and wherein said halogen substituent ischlorine or bromine, and said (₁–C₈)-alkyl substituent is methyl, wherethe methyl radical for its part optionally may be mono- orpolysubstituted by fluorine.
 11. The process of claim 7 wherein inprocess alternative “A”, the corresponding carbonyl halide of carboxylicacid (III) is a carbonyl chloride.
 12. The process of claim 7 wherein inprocess alternative “B”, the phosgene equivalent employed in thecyclization of compound (VII) is carbonyldimidazole (CDI).
 13. A methodfor treatment of a thromboembolic disorder comprising administering to apatient in need thereof an effective amount of a compound of claim 1,wherein the thromboembolic disorder is myocardial infarct, pulmonaryembolism or deep venous thrombosis.
 14. The compound of claim 6 that ispurified and isolated.
 15. A racemic mixture of a compound having thefollowing formula

and its enantiomer, or a pharmaceutically acceptable salt or hydratethereof.
 16. A compound having the following formula:


17. A pharmaceutical composition comprising the compound of claim 6 andone or more pharmacologically acceptable auxiliaries or excipients. 18.A pharmaceutical composition comprising the compound of claim 14 and oneor more pharmacologically acceptable auxiliaries or excipients.
 19. Apharmaceutical composition comprising the compound of claim 16 and oneor more pharmacologically acceptable auxiliaries or excipients.
 20. Theprocess of claim 7 wherein the substituted oxazolidinone that isprepared is

or a pharmaceutically acceptable salt or hydrate thereof.
 21. A processfor the preparation of the compound of claim 6 comprising reacting acompound of the following formula

with 5-chlorothiophene-2-carbonyl chloride in an inert solvent toprepare the compound of claim
 6. 22. The process of claim 21 wherein theinert solvent comprises pyridine.
 23. A method for the treatment ofatherosclerosis comprising administering an effective amount of thecomposition of claim 17 to a patient in need thereof.
 24. A method forthe treatment of myocardial infarct, pulmonary embolism or deep venousthrombosis comprising administering an effective amount of thecomposition of claim 17 to a patient in need thereof.
 25. A method forthe treatment of atherosclerosis comprising administering an effectiveamount of the composition of claim 18 to a patient in need thereof. 26.A method for the treatment of myocardial infarct, pulmonary embolism ordeep venous thrombosis comprising administering an effective amount ofthe composition of claim 18 to a patient in need thereof.
 27. Acomposition comprising a compound having formula (a):

or a pharmaceutically acceptable salt or hydrate thereof, wherein thecomposition is substantially free of the enantiomer of the compound offormula (a) and substantially free of the salts and hydrates of theenantiomer of the compound of formula (a).
 28. A pharmaceuticalcomposition comprising the composition of claim 27 and one or morepharmacologically acceptable auxiliaries or excipients.
 29. A method forthe treatment of atherosclerosis comprising administering an effectiveamount of the composition of claim 28 to a patient in need thereof. 30.A method for the treatment of myocardial infarct, pulmonary embolism ordeep venous thrombosis comprising administering an effective amount ofthe composition of claim 28 to a patient in need thereof.